Pyrazolopyridine compounds and uses thereof

ABSTRACT

Disclosed are compounds of Formula (I), methods of using the compounds for inhibiting HPK1 activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with HPK1 activity such as cancer.

FIELD OF THE INVENTION

The disclosure provides compounds as well as their compositions andmethods of use. The compounds modulate hematopoietic progenitor kinase 1(HPK1) activity and are useful in the treatment of various diseasesincluding cancer.

BACKGROUND OF THE INVENTION

Hematopoietic progenitor kinase 1 (HPK1) originally cloned fromhematopoietic progenitor cells is a member of MAP kinase kinase kinasekinases (MAP4Ks) family, which includes MAP4K1/HPK1, MAP4K2/GCK,MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK (Hu, M. C., et al.,Genes Dev, 1996. 10(18): p. 2251-64). HPK1 is of particular interestbecause it is predominantly expressed in hematopoietic cells such as Tcells, B cells, macrophages, dendritic cells, neutrophils, and mastcells (Hu, M. C., et al., Genes Dev, 1996. 10(18): p. 2251-64; Kiefer,F., et al., EMBO J, 1996. 15(24): p. 7013-25). HPK1 kinase activity hasbeen shown to be induced upon activation of T cell receptors (TCR)(Liou, J., et al., Immunity, 2000. 12(4): p. 399-408), B cell receptors(BCR) (Liou, J., et al., Immunity, 2000. 12(4): p. 399-408),transforming growth factor receptor (TGF-βR) (Wang, W., et al., J BiolChem, 1997. 272(36): p. 22771-5; Zhou, G., et al., J Biol Chem, 1999.274(19): p. 13133-8), or G_(s)-coupled PGE2 receptors (EP2 and EP4)(Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96). As such,HPK1 regulates diverse functions of various immune cells.

HPK1 is important in regulating the functions of various immune cellsand it has been implicated in autoimmune diseases and anti-tumorimmunity (Shui, J. W., et al., Nat Immunol, 2007. 8(1): p. 84-91; Wang,X., et al., J Biol Chem, 2012. 287(14): p. 11037-48). HPK1 knockout micewere more susceptible to the induction of experimental autoimmuneencephalomyelitis (EAE) (Shui, J. W., et al., Nat Immunol, 2007. 8(1):p. 84-91). In human, HPK1 was downregulated in peripheral bloodmononuclear cells of psoriatic arthritis patients or T cells of systemiclupus erythematosus (SLE) patients (Batliwalla, F. M., et al., Mol Med,2005. 11(1-12): p. 21-9). Those observations suggested that attenuationof HPK1 activity may contribute to autoimmunity in patients.Furthermore, HPK1 may also control anti-tumor immunity via Tcell-dependent mechanisms. In the PGE2-producing Lewis lung carcinomatumor model, the tumors developed more slowly in HPK1 knockout mice ascompared to wild-type mice (see US 2007/0087988). In addition, it wasshown that adoptive transfer of HPK1 deficient T cells was moreeffective in controlling tumor growth and metastasis than wild-type Tcells (Alzabin, S., et al., Cancer Immunol Immunother, 2010. 59(3): p.419-29). Similarly, BMDCs from HPK1 knockout mice were more efficient tomount a T cell response to eradicate Lewis lung carcinoma as compared towild-type BMDCs (Alzabin, S., et al., J Immunol, 2009. 182(10): p.6187-94). These data, in conjunction with the restricted expression ofHPK1 in hematopoietic cells and lack of effect on the normal developmentof immune cells, suggest that HPK1 may be an excellent drug target forenhancing antitumor immunity. Accordingly, there is a need for newcompounds that modulate HPK1 activity.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

The present disclosure further provides a pharmaceutical compositioncomprising a compound of the disclosure, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient.

The present disclosure further provides methods of inhibiting HPK1activity, which comprises administering to an individual a compound ofthe disclosure, or a pharmaceutically acceptable salt thereof.

The present disclosure further provides methods of treating a disease ordisorder in a patient comprising administering to the patient atherapeutically effective amount of a compound of the disclosure, or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

Compounds

The present disclosure provides, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from Cy¹, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NOR^(a))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰;

Cy¹ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein each 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R²⁰;

R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃-10 cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆-10 aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R³⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1)NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1) S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

or two R¹⁰ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a3), SR^(a3), C(O)R^(b3)C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆-10 aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(b5)R^(d5); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆-10 aryl,5-10 membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NOR^(a2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆-10 aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a4), SR^(a4), C(O)R^(b4)C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or two R²¹ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7 membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a8), SR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)(O)OR^(a8), NR^(c8) S(O)R^(b8),NR^(c8)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8),S(O)NR^(c8)R^(d8), S(O)₂R^(b8), and S(O)₂NR^(c8)R^(d8); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a) and R^(c) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

each R^(d) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

or any R^(c) and R^(d) attached to the same N atom, together with the Natom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

each R^(b) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamoyl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl,are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamoyl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a2), R^(c2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

each R^(e2) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamoyl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²²;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²²;

each R^(a5), R^(c5) and R^(d5), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a6), R^(c6) and R^(d6), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃-10 cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl,are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰;

or any R^(c7) and R^(d7) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R³⁰;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³⁰;

each R^(a8), R^(c8) and R^(d8), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

or any R^(c8) and R^(d8) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R^(g);

each R^(b8) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamoyl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

provided that:

1) R¹ is other than CH₃;

2) R¹ is other than 2-morpholinopyridin-4-yl;

3) when Cy^(A) is phenyl, then R¹ is other than(2-chloropyridin-4-yloxy)methyl; and

4) when R¹ is halogen-substituted phenyl, then Cy^(A) is other thanunsubstituted or substituted 4H-1,2,4-triazol-3-yl.

In some embodiments, R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), and NR^(c)C(O)OR^(a); wherein said C₂₋₆ alkenyl andC₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰.

In some embodiments, R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, and CN; wherein said C₂₋₆ alkenyl andC₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰.

In some embodiments, R¹ is selected from Cy¹, C₂₋₆ alkenyl, and C₂₋₆alkynyl; wherein said C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹⁰.

In some embodiments, R¹ is Cy¹.

In some embodiments, R¹ is selected from Cy¹, C(O)NR^(c)R^(d) andNR^(c)C(O)R^(b). In some embodiments, R¹ is selected from phenyl,pyridinyl, pyrazolyl, thiazolyl, C(O)NR^(c)R^(d) and NR^(c)C(O)R^(b);wherein the phenyl, pyridinyl, pyrazolyl, and thiazolyl are eachoptionally substituted with 1, 2 or 3 substituents independentlyselected from R¹⁰.

In some embodiments, Cy¹ is selected from C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein the 5-10 membered heteroaryl has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl is optionally substituted by oxo to form a carbonyl group;and wherein the C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰.

In some embodiments, Cy¹ is selected from phenyl and 5-6 memberedheteroaryl; wherein the 5-6 membered heteroaryl has at least onering-forming carbon atom and 1, 2 or 3 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of 5-6 membered heteroaryl is optionally substituted by oxo to forma carbonyl group; and wherein the phenyl and 5-6 membered heteroaryl areeach optionally substituted with 1, 2 or 3 substituents independentlyselected from R¹⁰.

In some embodiments, Cy¹ is phenyl, pyridinyl, pyrazolyl, orpyrimidinyl; wherein the phenyl, pyridinyl, pyrazolyl, or pyrimidinylare each optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹⁰.

In some embodiments, Cy¹ is phenyl, pyridin-4-yl, 1H-pyrazol-4-yl,pyridin-3-yl, or pyrimidin-5-yl; wherein the phenyl, pyridin-4-yl,1H-pyrazol-4-yl, pyridin-3-yl, or pyrimidin-5-yl are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹⁰.

In some embodiments, Cy¹ is pyrazolyl (e.g., 1H-pyrazol-4-yl) optionallysubstituted with 1 or 2 C₁₋₆ alkyl (e.g., methyl). In some embodiments,Cy¹ is 1-methyl-1H-pyrazol-4-yl.

In some embodiments, Cy¹ is phenyl, pyridin-4-yl, or 1H-pyrazol-4-yl;wherein the phenyl, pyridin-4-yl, and 1H-pyrazol-4-yl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,CN, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),NR^(c1)R^(d1), and NR^(c1)C(O)R^(b1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,4-10 membered heterocycloalkyl, C(O)R^(b1), and C(O)NR^(c1)R^(d1);wherein said C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,piperazinyl, piperidinyl, morpholinyl, C(O)R^(b1), andC(O)NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, piperazinyl, and piperidinylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹.

In some embodiments, R¹⁰ is morpholinyl optionally substituted with 1,2, 3, or 4 substituents independently selected from R¹¹. In someembodiments, R¹ is 2-morpholinopyrimidin-5-yl.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,piperazinyl, piperidinyl, C(O)R^(b1), and C(O)NR^(c1)R^(d1); whereinsaid C₁₋₆ alkyl, piperazinyl, and piperidinyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹.

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, OR^(a3), C(O)R^(b3),and S(O)₂R^(b3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, C(O)R^(b3), andS(O)₂R^(b3); wherein said C₁₋₆ alkyl, C₂-6 alkenyl, and C₂₋₆ alkynyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,OR^(a3)C(O)R^(b3), and S(O)₂R^(b3).

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C(O)R^(b3), and S(O)₂R^(b3).

In some embodiments, each R¹⁰ is independently selected from4-methylpiperazin-1-yl, N-methylaminocarbonyl, methyl,N-(1-methylpiperidin-4-yl)aminocarbonyl,(4-methylpiperazin-1-yl)carbonyl, N-phenylaminocarbonyl, piperidin-4-yl,1-(methylsulfonyl)piperidin-4-yl, 1-acetyl-piperidin-4-yl, morpholinyl,4-ethylpiperazin-1-yl, or 2-hydroxypropan-2-yl.

In some embodiments, each R¹⁰ is independently selected from4-methylpiperazin-1-yl, N-methylaminocarbonyl, methyl,N-(1-methylpiperidin-4-yl)aminocarbonyl,(4-methylpiperazin-1-yl)carbonyl, N-phenylaminocarbonyl, piperidin-4-yl,1-(methylsulfonyl)piperidin-4-yl, and 1-acetyl-piperidin-4-yl.

In some embodiments, Cy^(A) is C₆₋₁₀ aryl optionally substituted with 1,2, 3 or 4 substituents independently selected from R²⁰.

In some embodiments, Cy^(A) is 5-10 membered heteroaryl; wherein the5-10 membered heteroaryl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the 5-10membered heteroaryl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰.

In some embodiments, Cy^(A) is phenyl, 1H-indazol-4-yl, pyridin-3-yl,pyridin-4-yl, pyrimidin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl,pyridin-2(1H)-on-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl,pyrido[3,2-b]pyrazin-7-yl, oxazolo[5,4-c]pyridin-7-yl, 1H-pyrazol-4-yl,pyrazolo[1,5-a]pyridin-3-yl, quinolin-5-yl, isoquinolin-4-yl,1H-indol-4-yl, and imidazo[1,2-a]pyridin-8-yl, each of which isoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²⁰.

In some embodiments, Cy^(A) is phenyl optionally substituted with 1, 2,3 or 4 substituents independently selected from R²⁰; wherein optionallytwo adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 5- or 6-memberedheterocycloalkyl ring, or a fused C₄₋₆ cycloalkyl ring; wherein thefused 5- or 6-membered heterocycloalkyl ring each has at least onering-forming carbon atom and 1, 2 or 3 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each fused 5- or 6-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the fused 5- or6-membered heterocycloalkyl ring and fused C₄₋₆ cycloalkyl ring are eachoptionally substituted with 1, 2 or 3 substituents independentlyselected from R²¹.

In some embodiments, Cy^(A) is phenyl optionally substituted with 1, 2,3 or 4 substituents independently selected from R²⁰. In someembodiments, Cy^(A) is phenyl substituted with 1, 2, or 3 substituentsindependently selected from C₁₋₆ alkyl or halo, wherein said C₁₋₆ alkylis each optionally substituted NR^(c4)R^(d4). In some embodiments,Cy^(A) is phenyl substituted with methyl, fluoro, or methylaminomethyl.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃-10 cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR²,OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, CN, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), S(O)R^(b2), S(O)NR^(c2)R^(d2),S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹; or two adjacent R²⁰ substituents on the Cy^(A) ring,taken together with the atoms to which they are attached, form a fused4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused C₃₋₇cycloalkyl ring; wherein each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1,2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of each fused 4-, 5-, 6- or7-membered heterocycloalkyl ring is optionally substituted by oxo toform a carbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN, OR,C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), andNR^(c2)S(O)₂R^(b2); wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹.

In some embodiments, each R²⁰ is independently selected from methoxy,methyl, fluoro, trifluoromethyl, amino, methoxy, hydroxymethyl,ethoxycarbonyl, methanesulfonamido, hydroxyl, N-methylaminocarbonyl,dimethylamino, cyano, methoxycarbonyl, acetylamino, phenyl, 2-oxazolyl,tert-butyl, aminocarbonyl, N-benzylaminocarbonyl,N-(pyridin-4-ylmethyl)aminocarbonyl, ethyl, methylaminomethyl; or twoadjacent R²⁰ substituents on the Cy^(A) ring, taken together with theatoms to which they are attached, form a fused 5- or 6-memberedheterocycloalkyl ring, or a fused C₅ cycloalkyl ring; wherein each fused5- or 6-membered heterocycloalkyl ring has at least one ring-formingcarbon atom and 1 or 2 ring-forming heteroatoms independently selectedfrom N and O; wherein a ring-forming carbon atom of each fused 5- or6-membered heterocycloalkyl ring is optionally substituted by oxo toform a carbonyl group; and wherein the fused 5- or 6-memberedheterocycloalkyl ring and fused C₅ cycloalkyl ring are each optionallysubstituted with 1 or 2 substituents independently selected from amino,methylamino, 2-hydroxyethylamino, and N-benzylamino.

In some embodiments, each R²⁰ is independently selected from methoxy,methyl, fluoro, trifluoromethyl, amino, methoxy, hydroxymethyl,ethoxycarbonyl, methanesulfonamido, hydroxyl, N-methylaminocarbonyl,dimethylamino, cyano, methoxycarbonyl, acetylamino, phenyl, 2-oxazolyl,tert-butyl, aminocarbonyl, N-benzylaminocarbonyl,N-(pyridin-4-ylmethyl)aminocarbonyl, and ethyl;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 5- or 6-memberedheterocycloalkyl ring, or a fused C₅ cycloalkyl ring; wherein each fused5- or 6-membered heterocycloalkyl ring has at least one ring-formingcarbon atom and 1 or 2 ring-forming heteroatoms independently selectedfrom N and O; wherein a ring-forming carbon atom of each fused 5- or6-membered heterocycloalkyl ring is optionally substituted by oxo toform a carbonyl group; and wherein the fused 5- or 6-memberedheterocycloalkyl ring and fused C₅ cycloalkyl ring are each optionallysubstituted with 1 or 2 substituents independently selected from amino,methylamino, 2-hydroxyethylamino, and N-benzylamino.

In some embodiments, R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁-6 haloalkyl, halo, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³⁰.

In some embodiments, R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, and CN; wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R³⁰.

In some embodiments, R² is H, C₁₋₆ alkyl, or CN.

In some embodiments, R² is H or C₁₋₆ alkyl.

In some embodiments, R² is H. In some embodiments, R² is CN.

In some embodiments, provided herein is a compound having Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or4.

In some embodiments, provided herein is a compound having Formula IIb:

or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3.

In some embodiments, provided herein is a compound having Formula IIIa:

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula IIIb:

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound having Formula IVa:

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, or4 and y is 1, 2, 3, or 4.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, n is 3.

In some embodiments, m is 1.

In some embodiments, m is 2.

In some embodiments, y is 1.

In some embodiments, y is 2.

In some embodiments, y is 3.

In some embodiments:

Cy^(A) is phenyl substituted with 1, 2, or 3 substitutents selected fromC₁₋₆ alkyl and halo, wherein said C₁₋₆ alkyl is optionally substitutedwith NR^(c4)R^(d4);

R² is H or CN;

Cy¹ is 5-6 membered heteroaryl optionally substituted with C₁₋₆ alkyl orhalo; and

each of R^(c4) and R^(d4) is H or C₁₋₆ alkyl.

In some embodiments:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NOR^(a))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹⁰;

Cy¹ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein each 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereinthe 5-membered heteroaryl has at least one ring-forming carbon atom and1 or 2 ring-forming heteroatoms independently selected from N, O, and Sand the 6-10 membered heteroaryl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R²⁰;

R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, CN, OR^(a7), SR^(a7), C(O)R^(b7),C(O)NR^(c7)R^(d7), C(O)OR^(a7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7),NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7),and S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R³⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, piperazinyl, piperidinyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃-10 cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene,5-10 membered heteroaryl-C₁₋₃ alkylene, halo, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1)C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, piperazinyl, piperidinyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

or two R¹⁰ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆-10 aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a3), SR^(a3), C(O)R^(b3)C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3)NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆-10 aryl,5-10 membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆-10 aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NOR^(a2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2) S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆-10 aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆-10 aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or two R²¹ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7 membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a8), SR^(a8),C(O)R^(b8), C(O)NR^(c8)R^(d8), C(O)OR^(a8), NR^(c8)R^(d8),NR^(c8)C(O)R^(b8), NR^(c8)(O)OR^(a8), NR^(c8) S(O)R^(b8), NR^(c)S(O)₂R^(b8), NR^(c8)S(O)₂NR^(c8)R^(d8), S(O)R^(b8), S(O)NR^(c8)R^(d8),S(O)₂R^(b8), and S(O)₂NR^(c8)R^(d8); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryland 4-7 membered heterocycloalkyl, are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(a) and R^(c) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

each R^(d) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

or any R^(c) and R^(d) attached to the same N atom, together with the Natom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

each R^(b) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamoyl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl,are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamoyl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a2), R^(c2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

each R^(e2) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamoyl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆alkyl)carbamoyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl, are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²²;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²²;

each R^(a5), R^(c5) and R^(d5), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a6), R^(c6) and R^(d6), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl,are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R³⁰; or any R^(c7) and R^(d7) attached tothe same N atom, together with the N atom to which they are attached,form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2 or 3 substituents independently selected from R³⁰;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³⁰; each R^(a8), R^(c8) and R^(d8), is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

-   -   or any R^(c8) and R^(d8) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R^(g);

each R^(b8) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); and each R^(g) is independently selected from OH, NO₂, CN, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,C₃₋₆ cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamoyl, C₁₋₆ alkylcarbamoyl, di(C₁₋₆ alkyl)carbamoyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b),NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), andS(O)₂NR^(c)R^(d); wherein said C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰; Cy¹ is selected from C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein the 5-10 membered heteroaryl has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl is optionally substituted by oxo to form a carbonyl group;and wherein the C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereinthe 5-membered heteroaryl has at least one ring-forming carbon atom and1 or 2 ring-forming heteroatoms independently selected from N, O, and Sand the 6-10 membered heteroaryl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R²⁰;

R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7),C(O)OR^(a7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), and NR^(c7)C(O)OR^(a7);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, piperazinyl, piperidinyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), and S(O)₂NR^(c1)R^(dl); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, piperazinyl, piperidinyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), andS(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5)NR^(c5)C(O)OR^(a5), S(O)R^(b5), S(O)NR^(c5)R^(d5),S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 5- or 6-memberedheterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring; wherein eachfused 5- or 6-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each fused 5- or 6-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the fused 5- or6-membered heterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, CN, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), andS(O)₂NR^(c6)R^(d6); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g);

each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, phenyl, halo, CN, OR^(a8), SR^(a8), C(O)R^(b8),C(O)NR^(c8)R^(d8), C(O)OR^(a8), NR^(c8)R^(d8), NR^(c8)(O)R^(b8),NR^(C8)C(O)OR^(a8), S(O)R^(b8), S(O)NR^(c8)R^(d8), S(O)₂R^(b8), andS(O)₂NR^(c8)R^(d8); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and phenyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a) and R^(c) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹⁰;

each R^(d) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

each R^(b) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹⁰;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, 4-10 memberedheterocycloalkyl, and C₆₋₁₀ aryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, 4-10 membered heterocycloalkyl and C₆₋₁₀ aryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and 4-10 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(a2), R^(c2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹²;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R²²;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²²;

each R^(a5), R^(c5) and R^(d5), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl;

each R^(a6), R^(c6) and R^(d6), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl;

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a8), R^(c8) and R^(d8), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b8) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamoyl, C₁₋₆ alkylcarbamoyl,di(C₁₋₆ alkyl)carbamoyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, and di(C₁₋₆ alkyl)aminosulfonyl.

In some embodiments:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, and CN; wherein said C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

Cy¹ is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereinthe 5-membered heteroaryl has at least one ring-forming carbon atom and1 or 2 ring-forming heteroatoms independently selected from N, O, and Sand the 6-10 membered heteroaryl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R²⁰;

R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, and CN;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, piperazinyl, piperidinyl, halo, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), and NR^(c1)R^(d1); whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, piperazinyl, andpiperidinyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), and NR^(c2)S(O)₂R^(b2); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 5- or 6-memberedheterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring; wherein eachfused 5- or 6-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each fused 5- or 6-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the fused 5- or6-membered heterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),C(O)OR^(a6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), S(O)₂R^(b6), andS(O)₂NR^(c6)R^(d6);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, 4-10 memberedheterocycloalkyl, and C₆₋₁₀ aryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, 4-10 membered heterocycloalkyl and C₆₋₁₀ aryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and 4-10 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

each R^(a2), R^(c2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a4), R^(c4) and R^(d4), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R²²;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a6), R^(c6) and R^(d6), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; and each R^(b6) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆ haloalkyl.

In some embodiments:

R¹ is Cy¹;

Cy¹ is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereinthe 5-membered heteroaryl has at least one ring-forming carbon atom and1 or 2 ring-forming heteroatoms independently selected from N, O, and Sand the 6-10 membered heteroaryl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R²⁰;

R² is H;

each R¹⁰ is independently selected from C₁₋₆ alkyl, piperazinyl,piperidinyl, C(O)R^(b1) and C(O)NR^(c1)R^(d1); wherein said C₁₋₆ alkyl,piperazinyl, and piperidinyl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C(O)R^(b3), andS(O)₂R^(b3);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN, OR^(a2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), andNR^(c2)S(O)₂R^(b2); wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 5- or 6-memberedheterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring; wherein eachfused 5- or 6-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each fused 5- or 6-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the fused 5- or6-membered heterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²¹;

each R²¹ is independently selected from C₆₋₁₀ aryl, 5-10 memberedheteroaryl, OR^(a4), and NR^(c4)R^(d4);

each R²² is OR^(a6);

each R^(c1) and R^(d1) is independently selected from H, C₁₋₆ alkyl,4-10 membered heterocycloalkyl, and C₆₋₁₀ aryl; wherein said C₁₋₆ alkyl,4-10 membered heterocycloalkyl and C₆₋₁₀ aryl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

R^(b1) is 4-10 membered heterocycloalkyl optionally substituted with 1,2, 3, or 4 substituents independently selected from R¹¹;

each R^(a2), R^(c2) and R^(d2) is independently H or C₁₋₆ alkyl; whereinsaid C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹;

each R^(b2) is C₁₋₆ alkyl;

each R^(b3) is C₁₋₆ alkyl;

each R^(a4), R^(c4) and R^(d4) is H or C₁₋₆ alkyl; wherein said C₁₋₆alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²; and

R^(a6) is H.

In some embodiments:

R¹ is Cy¹;

Cy¹ is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereinthe 5-membered heteroaryl has at least one ring-forming carbon atom and1 or 2 ring-forming heteroatoms independently selected from N, O, and Sand the 6-10 membered heteroaryl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3 or 4 substituents independently selected from R²⁰;

R² is H or CN;

each R¹⁰ is independently selected from C₁₋₆ alkyl, piperazinyl,piperidinyl, C(O)R^(b1) and C(O)NR^(c1)R^(d1); wherein said C₁₋₆ alkyl,piperazinyl, and piperidinyl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, OR^(a3), C(O)R^(b3),and S(O)₂R^(b3);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN, OR^(a2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), andNR^(c2)S(O)₂R^(b2); wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 5- or 6-memberedheterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring; wherein eachfused 5- or 6-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each fused 5- or 6-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the fused 5- or6-membered heterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²¹;

each R²¹ is independently selected from C₆₋₁₀ aryl, 5-10 memberedheteroaryl, OR^(a4), and NR^(c4)R^(d4);

each R²² is OR^(a6);

each R^(c1) and R^(d1) is independently selected from H, C₁₋₆ alkyl,4-10 membered heterocycloalkyl, and C₆₋₁₀ aryl; wherein said C₁₋₆ alkyl,4-10 membered heterocycloalkyl and C₆₋₁₀ aryl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹;

R^(b1) is 4-10 membered heterocycloalkyl optionally substituted with 1,2, 3, or 4 substituents independently selected from R¹¹;

each R^(a2), R^(c2) and R^(d2) is independently H or C₁₋₆ alkyl; whereinsaid C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹;

each R^(b2) is C₁₋₆ alkyl;

each R^(b3) is C₁₋₆ alkyl;

each R^(a3) is independently H or C₁₋₆ alkyl;

each R^(a4), R^(c4) and R^(d4) is H or C₁₋₆ alkyl; wherein said C₁₋₆alkyl is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²; and

R^(a6) is H.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds ofFormula (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)— includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl,” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chained orbranched. The term “C_(n-m) alkyl”, refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl,” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl,” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene,” employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, ethan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl,propan-1,1-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl,2-methyl-propan-1,3-diyl and the like.

The term “alkoxy,” employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

The term “amino” refers to a group of formula —NH₂.

The term “carbonyl,” employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula —C≡N, whichalso may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m) haloalkyl” refers to a C_(n-m) alkyl group having n tom carbon atoms and from at least one up to {2(n to m)+1} halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments,the haloalkyl group is a fluoroalkyl group.

The term “haloalkoxy,” employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, and the like. In some embodiments, arylgroups have from 6 to about 10 carbon atoms. In some embodiments arylgroups have 6 carbon atoms. In some embodiments aryl groups have 10carbon atoms. In some embodiments, the aryl group is phenyl. In someembodiments, the aryl group is naphthyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3 or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-10 ring atomsincluding carbon atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanyl,thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-,1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine),indolyl, indazolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl, purinyl, pyrrolopyridinyl, pyrazolopyridinyl,imidazopyridinyl, pyridopyridinyl, pyridopyrazinyl, oxazolopyridinyl andthe like. In some embodiments, the heteroaryl group is pyridone (e.g.,2-pyridone).

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term “cycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic hydrocarbon ring system (monocyclic,bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C₃₋₇).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally oxidized to form an oxo orsulfido group. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic ring or ring system, which mayoptionally contain one or more alkenylene groups as part of the ringstructure, which has at least one heteroatom ring member independentlyselected from nitrogen, sulfur oxygen and phosphorus, and which has 4-10ring members, 4-7 ring members, or 4-6 ring members. Included within theterm “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-memberedheterocycloalkyl groups. Heterocycloalkyl groups can include mono- orbicyclic (e.g., having two fused or bridged rings) or spirocyclic ringsystems. In some embodiments, the heterocycloalkyl group is a monocyclicgroup having 1, 2 or 3 heteroatoms independently selected from nitrogen,sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of aheterocycloalkyl group can be optionally oxidized to form an oxo orsulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) orS(O)₂, N-oxide etc.) or a nitrogen atom can be quaternized. Theheterocycloalkyl group can be attached through a ring-forming carbonatom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the heterocycloalkyl ring, e.g., benzo or thienyl derivativesof piperidine, morpholine, azepine, etc. A heterocycloalkyl groupcontaining a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. Examples of heterocycloalkyl groups include azetidinyl, azepanyl,dihydrobenzofuranyl, dihydrobenzodioxine, dihydrofuranyl,dihydropyranyl, dihydropyrolopyridinyl, morpholino,3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl,piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, tropanyl,and thiomorpholino.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as(3-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art (Deuterium Labeling in OrganicChemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts,1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau,Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007,7744-7765; The Organic Chemistry of Isotopic Labelling by James R.Hanson, Royal Society of Chemistry, 2011). Isotopically labeledcompounds can used in various studies such as NMR spectroscopy,metabolism experiments, and/or assays.

Substitution with heavier isotopes such as deuterium, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. (A. Kerekes et.al. J. Med.Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm. 2015,58, 308-312).

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted. The term is also meant to refer to compounds of theinventions, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J.Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of Formula (I) can be prepared, e.g., using a process asillustrated in the schemes below. Compounds of Formula (I) with avarious substitutions at position R¹ such as those described herein canbe prepared, using a process as illustrated in Scheme 1. In the processdepicted in Scheme 1, the halo substituent in compounds of Formula 1-1can be converted into Cy^(A) via a number of different cross-couplingreactions, including Suzuki (e.g., in the presence of a palladiumcatalyst, such as Xphos Pd G2, and a base, such as potassium phosphate),Negishi and Stille (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0)), Cu-catalyzedamination (e.g., in the presence of Cu catalyst and a ligand, such asCuI and phenanthroline, and a base, such as cesium carbonate orpotassium carbonate), and others, to give compounds of Formula 1-2.These compounds can be further halogenated with a halogenation agent(e.g., NIS or iodine) to form compounds of Formula 1-3. The halogensubstituent in the compounds of Formula 1-3 can be converted into R¹ viaa number of different cross-coupling reactions, including Stille (ACSCatalysis 2015, 5, 3040-3053) Suzuki (Tetrahedron 2002, 58, 9633-9695),Sonogashira (Chem. Soc. Rev. 2011, 40, 5084-5121), Negishi (ACSCatalysis 2016, 6, 1540-1552), Buchwald-Hartwig amination (Chem. Sci.2011, 2, 27-50), Cu-catalyzed amination (Org. React. 2014, 85, 1-688)and others, to give the desired compounds of Formula (I).

Alternatively, for the exploration of the substitution at positionCy^(A), compounds of Formula (I) can be prepared, using a process asillustrated in Scheme 2. Iodination of the compounds of Formula 1-1 withan iodination agent, such as iodine or NIS, forms compounds of Formula2-2. The iodo substituent in the compounds of Formula 2-2 can beconverted into R¹ via a number of different cross-coupling reactions,including Suzuki, Sonogashira, Negishi, Buchwald-Hartwig amination,Cu-catalyzed amination and others, to give the compounds of Formula 2-3.The chloro substituent in the compounds of Formula 2-3 can be furtherconverted into Cy^(A) via a number of different cross-couplingreactions, including Suzuki, Stille, Negishi, Cu-catalyzed amination andothers, to give the desired compounds of Formula (I).

Compounds of Formula (Ia) (compounds of Formula I wherein R¹ isNR^(c)(O)R^(b)) can be prepared, using a process as illustrated inScheme 3. In the process depicted in Scheme 3, compounds of Formula 3-1react which hydroxylamine hydrochloride to form oxime intermediates,which are further converted to compounds of Formula 3-2 under thestandard conditions (e.g. under treatment with cyanuric chloride).Cyclization upon treatment of the compounds of Formula 3-2 withhydrazine hydrate results in compounds of Formula 3-3. The NH group ofthe pyrazole ring of the compounds of Formula 3-3 is protected with asuitable protecting group (e.g., Boc) to form compounds of Formula 3-4.The halo substituent in the compounds of Formula 3-4 can be furtherconverted into Cy^(A) via a number of different cross-couplingreactions, including Suzuki, Stille, Negishi, Cu-catalyzed amination,and others, to give the compounds of Formula 3-5. Compounds of Formula3-5 react with different acid chlorides in a presence of base, such astriethylamine or DIPEA, to form compounds of Formula 3-6. Finally,deprotection of the protecting group, e.g. under acidic conditions, suchas treatment with HCl or TFA, results in the formation of the desiredcompounds of Formula (Ia). Alternatively compounds of Formula 3-6 can bealkylated or arylated and then deprotected to prepare amides whereinR^(c) is other than hydrogen.

Compounds of Formula (Ib) (compounds of Formula I wherein R¹ isC(O)NR^(c)R^(d)) can be prepared, using a process as illustrated inScheme 4. In the process depicted in Scheme 4, compounds of Formula 4-2are formed after protection of the NH group of the compounds of Formula1-3 with a suitable protecting group (e.g. SEM or Boc). The compounds ofFormula 4-2 are converted into compounds of Formula 4-3 underPd-catalyzed carbonylation conditions, such as in a presence of Pdcatalyst (e.g., Pd(dppf)Cl₂*DCM) and base (e.g., triethylamine) undercarbon monoxide atmosphere. Hydrolysis of the ester group under basicconditions, such as LiOH or NaOH, forms the compounds of Formula 4-4.Compounds of the Formula 4-4 can be coupled to an amine, HNR^(c)R^(d),using standard amide coupling agents (e.g., HBTU, HATU or EDC) to givecompounds of Formula 4-5. Finally, deprotection of the protecting group,e.g. under acidic conditions, such as treatment with HCl or TFA, resultsin the formation of the desired compounds of Formula (Ib).

Compounds of Formula (I) with various substitutions at position R² suchas those described herein can be prepared, using a process asillustrated in Scheme 5. In the process depicted in Scheme 5,bromination of 5-chloro-2-methylpyridin-3-amine 5-1 with a brominatingagent (e.g., bromine or NBS) forms compounds of Formula 5-2. Acylationof the NH₂ group in the compounds of Formula 5-2 with acylating agents(e.g., Ac₂O or AcCl) followed by the treatment with amyl nitrite formscompounds of Formula 5-3. These compounds can be further iodinated withan iodinating agent (e.g., NIS or iodine) to form compounds of Formula5-4. The NH group of the pyrazole ring in the compounds of Formula 5-4is protected with a suitable protecting group, such as Boc or SEM, toform compounds of Formula 5-5. The iodo substituent in the compounds ofFormula 5-5 can be converted into R¹ via a number of differentcross-coupling reactions, including Suzuki, Stille, Negishi,Cu-catalyzed amination, and others, to give the compounds of Formula5-6. The bromo substituent in the compounds of Formula 5-6 can befurther converted into Cy^(A) via a number of different cross-couplingreactions, including Suzuki, Stille, Negishi, and others, to give thecompounds of Formula 5-7. The chloro substituent in the compounds ofFormula 5-7 can be further converted into R² via a number of differentcross-coupling reactions, including Suzuki, Stille, Negishi, and others,to give the compounds of Formula 5-8. Finally, deprotection of theprotecting group, e.g. under acidic conditions, such as treatment withHCl or TFA, results in the formation of the desired compounds of Formula(I).

Compounds of Formula (Ic) with the cyano group at position R² such asthose described herein can be prepared, using a process as illustratedin Scheme 6. In the process depicted in Scheme 6, protection of6-bromo-1H-pyrazolo[4,3-b]pyridine 6-1 with a suitable protecting group(e.g., trityl, SEM, boc and others) forms compounds of Formula 6-2.Treating the compounds of Formula 6-2 with m-CPBA forms compounds ofFormula 6-3 which could be further converted into compounds of Formula6-4 via Pd-catalyzed cyanation. Upon treating with base (eg. Et₃N or^(i)Pr₂EtN) and oxalyl dichloride, the compounds of Formula 6-4 areconverted into compounds of Formula 6-5. The chloro substituent in thecompounds of Formula 6-5 can be converted into Cy^(A) via a number ofdifferent cross-coupling reactions, including Suzuki, Stille, Negishi,and others, to give the compounds of Formula 6-6. Removal of theprotecting group in the compounds of Formula 6-6 (e.g. under acidicconditions, such as treatment with HCl or TFA) gives compounds ofFormula 6-7. These compounds can be further halogenated with one of thehalogenation agents (e.g., NIS or iodine) to form compounds of formula6-8. Upon protection with a suitable protecting group (e.g., Boc, SEMand others), the compounds of Formula 6-8 are converted into compoundsof Formula 6-9. The iodo substituent in the compounds of Formula 6-9 canbe further converted into R¹ via a number of different cross-couplingreactions, including Suzuki, Stille, Sonogashira, Negishi,Buchwald-Hartwig amination, Cu-catalyzed amination and others, to givethe compounds of Formula 6-10. Finally, deprotection of the protectinggroup, e.g. under acidic conditions, such as treatment with HCl or TFA,results in the formation of the desired compounds of Formula (Ic).

HPK1 Kinase

Extensive studies have established that HPK1 is a negative regulator ofT cell and B cell activation (Hu, M. C., et al., Genes Dev, 1996.10(18): p. 2251-64; Kiefer, F., et al., EMBO J, 1996. 15(24): p.7013-25). HPK1-deficient mouse T cells showed dramatically increasedactivation of TCR proximal signaling, enhanced IL-2 production, andhyper-proliferation in vitro upon anti-CD3 stimulation (Shui, J. W., etal., Nat Immunol, 2007. 8(1): p. 84-91). Similar to T cells, HPK1knockout B cells produced much higher levels of IgM and IgG isoformsafter KLH immunization and displayed hyper-proliferation potentially asa result of enhanced BCR signaling. Wang, X., et al., J Biol Chem, 2012.287(14): p. 11037-48. Mechanistically, during TCR or BCR signaling, HPK1is activated by LCK/ZAP70 (T cells) or SYK/LYN (B cells) mediated-Tyr379phosphorylation and its subsequent binding to adaptor protein SLP-76 (Tcells) or BLNK (B cells) (Wang, X., et al., J Biol Chem, 2012. 287(14):p. 11037-48). Activated HPK1 phosphorylates SLP-76 on Ser376 or BLNK onThr152, leading to the recruitment of signaling molecule 14-3-3 andultimate ubiquitination-mediated degradation of SLP-76 or BLNK (Liou,J., et al., Immunity, 2000. 12(4): p. 399-408; Di Bartolo, V., et al., JExp Med, 2007. 204(3): p. 681-91). As SLP-76 and BLNK are essential forTCR/BCR-mediated signaling activation (e.g. ERK, phospholipase Cγ1,calcium flux, and NFAT activation), HPK1-mediated downregulation ofthese adaptor proteins provide a negative feedback mechanism toattenuate signaling intensity during T cell or B cell activation (Wang,X., et al., J Biol Chem, 2012. 287(14): p. 11037-48).

The bone marrow-derived dendritic cells (BDMCs) from HPK1 knockout miceshowed higher expression of co-stimulatory molecules (e.g. CD80/CD86)and enhanced production of proinflammatory cytokines (IL-12, TNF-α etc),and demonstrated superior ability to stimulate T cell proliferation invitro and in vivo as compared to wild-type DCs (Alzabin, S., et al., JImmunol, 2009. 182(10): p. 6187-94). These data suggest that HPK1 isalso an important negative regulator of dendritic cell activation(Alzabin, S., et al., J Immunol, 2009. 182(10): p. 6187-94). However,the signaling mechanisms underlying HPK-1 mediated negative regulationof DC activation remains to be elucidated.

In contrast, HPK1 appears to be a positive regulator of suppressivefunctions of regulatory T cells (Treg) (Sawasdikosol, S. et al., Thejournal of immunology, 2012. 188(supplement 1): p. 163). HPK1 deficientmouse Foxp3+ Tregs were defective in suppressing TCR-induced effector Tcell proliferation, and paradoxically gained the ability to produce IL-2following TCR engagement (Sawasdikosol, S. et al., The Journal ofImmunology, 2012. 188(supplement 1): p. 163). These data suggest thatHPK1 is an important regulator of Treg functions and peripheralself-tolerance.

HPK1 was also involved in PGE2-mediated inhibition of CD4+ T cellactivation (Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96).Studies published in US 2007/0087988 indicated that HPK1 kinase activitywas increased by exposure to physiological concentrations of PGE2 inCD4+ T cells and this effect was mediated by PEG2-induced PKAactivation. The proliferation of HPK1 deficient T cells was resistant tothe suppressive effects of PGE2 (see US 2007/0087988). Therefore,PGE2-mediated activation of HPK1 may represent a novel regulatorypathway of modulating immune response.

Uses of the Compounds

The present disclosure provides methods of modulating (e.g., inhibiting)HPK1 activity, said method comprising administering to a patient acompound provided herein, or a pharmaceutically acceptable salt thereof.In certain embodiments, the compounds of the present disclosure, orpharmaceutically acceptable salts thereof, are useful for therapeuticadministration to enhance, stimulate and/or increase immunity in cancer.For example, a method of treating a disease or disorder associated withinhibition of HPK1 interaction can include administering to a patient inneed thereof a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable salt thereof. The compounds ofthe present disclosure can be used alone, in combination with otheragents or therapies or as an adjuvant or neoadjuvant for the treatmentof diseases or disorders, including cancers. For the uses describedherein, any of the compounds of the disclosure, including any of theembodiments thereof, may be used.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, triple-negativebreast cancer, colon cancer and lung cancer (e.g. non-small cell lungcancer and small cell lung cancer). Additionally, the disclosureincludes refractory or recurrent malignancies whose growth may beinhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasiasyndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiplemyeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia,hairy cell lymphoma, chronic myelogenic lymphoma and Burkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), and spinal cord (neurofibroma, meningioma, glioma,sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In someembodiments, diseases and indications that are treatable using thecompounds of the present disclosure include, but are not limited to,sickle cell disease (e.g., sickle cell anemia), triple-negative breastcancer (TNBC), myelodysplastic syndromes, testicular cancer, bile ductcancer, esophageal cancer, and urothelial carcinoma.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers.

In some embodiments, HPK1 inhibitors may be used to treat tumorsproducing PGE2 (e.g. Cox-2 overexpressing tumors) and/or adenosine (CD73and CD39 over-expressing tumors). Overexpression of Cox-2 has beendetected in a number of tumors, such as colorectal, breast, pancreaticand lung cancers, where it correlates with a poor prognosis.Overexpression of COX-2 has been reported in hematological cancer modelssuch as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia)as well as in patient's blast cells. CD73 is up-regulated in varioushuman carcinomas including those of colon, lung, pancreas and ovary.Importantly, higher expression levels of CD73 are associated with tumorneovascularization, invasiveness, and metastasis and with shorterpatient survival time in breast cancer.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions.

Examples of agents that may be combined with compounds of the presentdisclosure include inhibitors of the PI3K-AKT-mTOR pathway, inhibitorsof the Raf-MAPK pathway, inhibitors of JAK-STAT pathway, inhibitors ofbeta catenin pathway, inhibitors of notch pathway, inhibitors ofhedgehog pathway, inhibitors of Pim kinases, and inhibitors of proteinchaperones and cell cycle progression. Targeting more than one signalingpathway (or more than one biological molecule involved in a givensignaling pathway) may reduce the likelihood of drug-resistance arisingin a cell population, and/or reduce the toxicity of treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors for the treatmentof diseases, such as cancer. Examples of cancers include solid tumorsand liquid tumors, such as blood cancers. For example, the compounds ofthe present disclosure can be combined with one or more inhibitors ofthe following kinases for the treatment of cancer: Alai, Akt2, Akt3,TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK,MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR,CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4,c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2,EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK,ABL, ALK and B-Raf. In some embodiments, the compounds of the presentdisclosure can be combined with one or more of the following inhibitorsfor the treatment of cancer. Non-limiting examples of inhibitors thatcan be combined with the compounds of the present disclosure fortreatment of cancers include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 orFGFR4, e.g., AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258,lucitanib, dovitinib, TAS-120, JNJ-42756493, Debio1347, INCB54828,INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g.,ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g.,epacadostat and NLG919), an LSD1 inhibitor (e.g., GSK2979552, INCB59872and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797and INCB50465), a PI3K-gamma inhibitor such as a PI3K-gamma selectiveinhibitor, a CSF1R inhibitor (e.g., PLX3397 and LY3022855), a TAMreceptor tyrosine kinases (Tyro-3, Axl, and Mer), an angiogenesisinhibitor, an interleukin receptor inhibitor, bromo and extra terminalfamily members inhibitors (for example, bromodomain inhibitors or BETinhibitors such as OTX015, CPI-0610, INCB54329 and INCB57643) and anadenosine receptor antagonist or combinations thereof. Inhibitors ofHDAC such as panobinostat and vorinostat. Inhibitors of c-Met such asonartumzumab, tivantnib, and INC-280. Inhibitors of BTK such asibrutinib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus. Inhibitors of Raf, such as vemurafenib anddabrafenib. Inhibitors of MEK such as trametinib, selumetinib andGDC-0973. Inhibitors of Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), PARP (e.g., olaparib) and Pim kinases(LGH447, INCB053914 and SGI-1776) can also be combined with compounds ofthe present disclosure.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors. Exemplary immune checkpointinhibitors include inhibitors against immune checkpoint molecules suchas CD20, CD27, CD28, CD39, CD40, CD122, CD96, CD73, CD47, OX40, GITR,CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1,PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule isa stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS,OX40, GITR and CD137. In some embodiments, the immune checkpointmolecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3,B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In someembodiments, the compounds provided herein can be used in combinationwith one or more agents selected from MR inhibitors, TIGIT inhibitors,LAIR′ inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR betainhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab. In some embodiments, the anti PD-1 antibody isSHR-1210.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CSF1R, e.g., an anti-CSF1R antibody. In someembodiments, the anti-CSF1R antibody is IMC-CS4 or RG7155.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, IMP321 or GSK2831781.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, MK1248, BMS-986156, MEDI1873or GWN323.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562,MEDI6469, MOXR0916, PF-04518600 or GSK3174998. In some embodiments, theOX40L fusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is MBG-453.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the compounds of the invention can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat andNGL919. An example of an arginase inhibitor is CB-1158.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

Compounds of the present disclosure can be used in combination with oneor more agents for the treatment of diseases such as cancer. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include bendamustine, nitrogen mustards, ethylenimine derivatives,alkyl sulfonates, nitrosoureas and triazenes, uracil mustard,chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan,chlorambucil, pipobroman, triethylene-melamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, and temozolomide. In some embodiments, theproteasome inhibitor is carfilzomib. In some embodiments, thecorticosteroid is dexamethasone (DEX). In some embodiments, theimmunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, oncolytic virotherapy and immunomodulating small molecules,including thalidomide or JAK1/2 inhibitor and the like. The compoundscan be administered in combination with one or more anti-cancer drugs,such as a chemotherapeutics. Example chemotherapeutics include any of:abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide,asparaginase, axitinib, azacitidine, bevacizumab, bexarotene,baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib,buparlisib, busulfan intravenous, busulfan oral, calusterone,capecitabine, carboplatin, carmustine, cediranib, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, crizotinib,cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin,dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine,degarelix, denileukin, denileukin diftitox, deoxycoformycin,dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolonepropionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin,erlotinib, estramustine, etoposide phosphate, etoposide, exemestane,fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil,flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin,goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, nofetumomab, oserelin, oxaliplatin, paclitaxel,pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin,ponatinib, prednisone, procarbazine, quinacrine, rasburicase,regorafenib, reloxafine, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur,temozolomide, teniposide, testolactone, thalidomide, thioguanine,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine,vincristine, vinorelbine, vorinostat and zoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB, antibodies to PD-1 andPD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.). Examples ofantibodies to PD-1 and/or PD-L1 that can be combined with compounds ofthe present disclosure for the treatment of cancer or infections such asviral, bacteria, fungus and parasite infections include, but are notlimited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.

Other anti-cancer agents include inhibitors of kinases associated cellproliferative disorder. These kinases include but not limited toAurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptorkinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3,JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk and SGK.

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

The compounds of the present disclosure can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolideA (NSC-675451) and B. Typical suitable protease inhibitors includesaquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639);nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475);DMP-450; BMS-2322623; ABT-378; and AG-1 549. Other antiviral agentsinclude hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and YissumProject No. 11607.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the presentdisclosure can be administered in the form of pharmaceuticalcompositions. Thus the present disclosure provides a compositioncomprising a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or a pharmaceutically acceptable salt thereof, or any of the embodimentsthereof, and at least one pharmaceutically acceptable carrier orexcipient. These compositions can be prepared in a manner well known inthe pharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is indicated and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the present disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers or excipients. In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel KOOLV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

Labeled Compounds and Assay Methods

The compounds of the present disclosure can further be useful ininvestigations of biological processes in normal and abnormal tissues.Thus, another aspect of the present invention relates to fluorescentdye, spin label, heavy metal or radio-labeled compounds provided hereinthat would be useful not only in imaging techniques but also in assays,both in vitro and in vivo, for localizing and quantitating HPK1 proteinin tissue samples, including human, and for identifying HPK1 ligands byinhibition binding of a labeled compound. Accordingly, the presentinvention includes HPK1 binding assays that contain such labeledcompounds.

The present invention further includes isotopically-substitutedcompounds of the disclosure. An “isotopically-substituted” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having the same atomic number but a differentatomic mass or mass number. Compounds of the invention may containisotopes in a natural abundance as found in nature. Compounds of theinvention may also have isotopes in amounts greater to that found innature, e.g., synthetically incorporating low natural abundance isotopesinto the compounds of the invention so they are enriched in aparticularly useful isotope (e.g., ²H and ¹³C). It is to be understoodthat a “radio-labeled” compound is a compound that has incorporated atleast one isotope that is radioactive (e.g., radionuclide), e.g., ³H and¹⁴C. Suitable radionuclides that may be incorporated in compounds of thepresent invention include but are not limited to ³H (also written as Tfor tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl,⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide thatis incorporated in the instant radio-labeled compounds will depend onthe specific application of that radio-labeled compound. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. For in vitro HPK1 labeling and competitionassays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, or ³⁵Swill generally be most useful. For radio-imaging applications ¹¹C, ¹⁸F,¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be mostuseful. Synthetic methods for incorporating radio-isotopes into organiccompounds are known in the art.

Specifically, a labeled compound of the invention can be used in ascreening assay to identify and/or evaluate compounds. For example, anewly synthesized or identified compound (i.e., test compound) which islabeled can be evaluated for its ability to bind a HPK1 protein bymonitoring its concentration variation when contacting with the HPK1,through tracking of the labeling. For example, a test compound (labeled)can be evaluated for its ability to reduce binding of another compoundwhich is known to bind to a HPK1 protein (i.e., standard compound).Accordingly, the ability of a test compound to compete with the standardcompound for binding to the HPK1 protein directly correlates to itsbinding affinity. Conversely, in some other screening assays, thestandard compound is labeled and test compounds are unlabeled.Accordingly, the concentration of the labeled standard compound ismonitored in order to evaluate the competition between the standardcompound and the test compound, and the relative binding affinity of thetest compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of diseases or disorders associated withthe activity of HPK1, such as cancer or infections, which include one ormore containers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), or any ofthe embodiments thereof. Such kits can further include one or more ofvarious conventional pharmaceutical kit components, such as, e.g.,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of HPK1 according to at least one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Hague, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature (see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature (See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)). Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

Example 1.3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-phenyl-1H-pyrazolo[4,3-b]pyridine

Step 1. 5-Chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine

To a solution of 5-chloro-1H-pyrazolo[4,3-b]pyridine (1.0 g, 6.5 mmol)in 1,4-dioxane (60 mL) was added potassium hydroxide (1.5 g, 26 mmol)and iodine (3.3 g, 13 mmol). The reaction was warmed up to 50° C. andstirred at that temperature for 4 hours. After this time the reactionmixture was cooled to r.t. and then poured into saturated sodiumthiosulfate solution (100 mL) and stirred for another 10 mins. Theresulting mixture was extracted with ethyl acetate (2×50 mL). Thecombined organic layers were dried over MgSO₄, filtered and concentratedto dryness. The residue was used in the next step without furtherpurification. LC-MS calculated for C₆H₄ClIN₃ (M+H)⁺: m/z=279.9; found279.9.

Step 2.5-Chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-h]pyridine

To a solution of the above intermediate in 1,4-dioxane (60 mL) and water(20 mL) was added potassium phosphate (2.76 g, 13.0 mmol),(4-(4-methylpiperazin-1-yl)phenyl)boronic acid (1.4 g, 6.5 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg,0.061 mmol). The reaction mixture was degassed and backfilled with N₂and then stirred at 90° C. for 15 hours. The reaction mixture was cooledto r.t., filtered and concentrated to dryness. The residue was purifiedby silica gel chromatography using 0-15% methanol in DCM to afford thedesired product as brownish solid (630 mg, 30% over two steps). LC-MScalculated for C₁₇H₁₉ClN₅ (M+H)⁺: m/z=328.1; found 328.1.

Step 3.3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-phenyl-1H-pyrazolo[4,3-b]pyridine

To a solution of5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine(20 mg, 0.061 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL) was added(2-fluoro-6-methylphenyl)boronic acid (14 mg, 0.092 mmol), potassiumphosphate (26 mg, 0.12 mmol) and(2′-aminobiphenyl-2-yl)(chloro)(dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene)palladium(10 mg, 0.013 mmol). The reaction was degassed and backfilled with N₂and warmed up to 90° C. The reaction mixture was stirred at 90° C. for15 hours. The reaction mixture was cooled to r.t., diluted withmethanol, filtered and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₃H₂₄N₅ (M+H)⁺: m/z=370.2;found 370.2.

Example 2.5-(2-Methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 2-methoxyphenylboronic acid instead of phenylboronicacid as starting material. LC-MS calculated for C₂₄H₂₆N₅O (M+H)⁺:m/z=400.2; found 400.2.

Example 3.3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-o-tolyl-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 2-methylphenylboronic acid instead of phenylboronicacid as starting material. LC-MS calculated for C₂₄H₂₆N₅ (M+H)⁺:m/z=384.2; found 384.2.

Example 4.5-(2-Fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 2-fluorophenylboronic acid instead of phenylboronicacid as starting material. LC-MS calculated for C₂₃H₂₃FN₅ (M+H)⁺:m/z=388.2; found 388.2.

Example 5.3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 2-(trifluoromethyl)phenylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₄H₂₃F₃N₅(M+H)⁺: m/z=438.2; found 438.2.

Example 6.2-Methyl-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)aniline

This compound was prepared according to the procedures described inExample 1, using 3-amino-2-methylphenylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₄H₂₇N₆(M+H)⁺: m/z=399.2; found 399.2.

Example 7.5-(2-Fluoro-6-methylphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 2-fluoro-6-methylphenylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₄H₂₅FN₅(M+H)⁺: m/z=402.2; found 402.2.

Example 8.5-(2-Fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 2-fluoro-6-methoxyphenylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₄H₂₅FN₅O(M+H)⁺: m/z=418.2; found 418.2. ¹H NMR (400 MHz, DMSO) δ 8.43-8.31 (m,2H), 8.11-8.02 (d, J=8.6 Hz, 1H), 7.53-7.44 (td, J=8.4, 6.7 Hz, 1H),7.44-7.37 (d, J=8.7 Hz, 1H), 7.16-7.13 (d, J=8.9 Hz, 2H), 7.06-7.02 (d,J=8.3 Hz, 1H), 7.00-6.93 (t, J=8.8 Hz, 1H), 4.02-3.87 (m, 2H), 3.83-3.70(s, 3H), 3.61-3.48 (d, J=11.7 Hz, 2H), 3.27-3.10 (m, 2H), 3.11-2.97 (m,2H), 2.93-2.80 (s, 3H).

Example 9.5-(2,3-Difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 2,3-difluorophenylboronic acid instead of phenylboronicacid as starting material. LC-MS calculated for C₂₃H₂₂F₂N₅ (M+H)⁺:m/z=406.2; found 406.2.

Example 10.5-(2,3-Difluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 2,3-difluoro-6-methoxyphenylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated forC₂₄H₂₄F₂N₅O (M+H)⁺: m/z=436.2; found 436.2.

Example 11.(3-Fluoro-2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)methanol

This compound was prepared according to the procedures described inExample 1, using 2-fluoro-6-(hydroxymethyl)phenylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₄H₂₅FN₅O(M+H)⁺: m/z=418.2; found 418.2.

Example 12. Ethyl2-fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzoate

This compound was prepared according to the procedures described inExample 1, using 3-(ethoxycarbonyl)-2-fluorophenylboronic acid insteadof phenylboronic acid as starting material. LC-MS calculated forC₂₆H₂₇FN₅O₂ (M+H)⁺: m/z=460.2; found 460.2.

Example 13.N-(2-Fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)methanesulfonamide

To a solution of2-fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)aniline(Example 6, 20 mg, 0.050 mmol) in tetrahydrofuran (1 mL) was addedN,N-diisopropylethylamine (20 mg, 0.15 mmol) followed by methanesulfonylchloride (12 mg, 0.1 mmol) and the reaction was stirred at r.t. for 1hour. After this time the reaction mixture was diluted with methanol,filtered and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LC-MS calculated for C₂₄H₂₆FN₆O₂S (M+H)⁺: m/z=481.2; found481.2.

Example 14.2-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)phenol

This compound was prepared according to the procedures described inExample 1, using 2-hydroxyphenylboronic acid instead of phenylboronicacid as starting material. LC-MS calculated for C₂₃H₂₄N₅O (M+H)⁺:m/z=386.2; found 386.2.

Example 15.5-(2,3-Dihydrobenzofuran-7-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 2,3-dihydrobenzofuran-7-ylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₅H₂₆N₅O(M+H)⁺: m/z=412.2; found 412.2.

Example 16.5-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 2,3-dihydrobenzo[b][1,4]dioxin-5-ylboronic acid insteadof phenylboronic acid as starting material. LC-MS calculated forC₂₅H₂₆N₅O₂ (M+H)⁺: m/z=428.2; found 428.2.

Example 17.N-Methyl-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzamide

This compound was prepared according to the procedures described inExample 1, using 3-(methylcarbamoyl)phenylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₅H₂₇N₆O(M+H)⁺: m/z=427.2; found 427.2.

Example 18.N,N-Dimethyl-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)aniline

This compound was prepared according to the procedures described inExample 1, using 3-(dimethylamino)phenylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₅H₂₉N₆(M+H)⁺: m/z=413.2; found 413.2.

Example 19.2-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzonitrile

This compound was prepared according to the procedures described inExample 1, using 2-cyanophenylboronic acid instead of phenylboronic acidas starting material. LC-MS calculated for C₂₄H₂₃N₆ (M+H)⁺: m/z=395.2;found 395.2.

Example 20. Methyl2-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzoate

This compound was prepared according to the procedures described inExample 1, using 2-(methoxycarbonyl)phenylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₅H₂₆N₅O₂(M+H)⁺: m/z=428.2; found 428.2.

Example 21.N-(2-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)acetamide

This compound was prepared according to the procedures described inExample 1, using 2-acetamidophenylboronic acid instead of phenylboronicacid as starting material. LC-MS calculated for C₂₅H₂₇N₆O (M+H)⁺:m/z=427.2; found 427.2.

Example 22.5-(Biphenyl-2-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using biphenyl-2-ylboronic acid instead of phenylboronic acidas starting material. LC-MS calculated for C₂₉H₂₈N₅ (M+H)⁺: m/z=446.2;found 446.2.

Example 23.5-(1H-Indazol-4-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 1H-indazol-4-ylboronic acid instead of phenylboronicacid as starting material. LC-MS calculated for C₂₄H₂₄N₇ (M+H)⁺:m/z=410.2; found 410.2.

Example 24.3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using pyridin-3-ylboronic acid instead of phenylboronic acidas starting material. LC-MS calculated for C₂₂H₂₃N₆ (M+H)⁺: m/z=371.2;found 371.2. ¹H NMR (400 MHz, DMSO) δ 9.50 (d, J=2.2 Hz, 1H), 8.82-8.72(m, 2H), 8.55-8.45 (m, 2H), 8.24-8.09 (m, 2H), 7.81-7.71 (dd, J=8.0, 5.0Hz, 1H), 7.26-7.16 (m, 2H), 4.07-3.89 (m, 2H), 3.65-3.47 (m, 2H),3.30-3.03 (m, 4H), 2.95-2.80 (s, 3H).

Example 25.3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(pyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using pyridin-4-ylboronic acid instead of phenylboronic acidas starting material. LC-MS calculated for C₂₂H₂₃N₆ (M+H)⁺: m/z=371.2;found 371.2.

Example 26.3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(pyrimidin-5-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using pyrimidin-5-ylboronic acid instead of phenylboronicacid as starting material. LC-MS calculated for C₂₁H₂₂N₇ (M+H)⁺:m/z=372.2; found 372.2.

Example 27.5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one

This compound was prepared according to the procedures described inExample 1, using 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-ylboronicacid instead of phenylboronic acid as starting material. LC-MScalculated for C₂₄H₂₄N₇O (M+H)⁺: m/z=426.2; found 426.2.

Example 28.1′-Methyl-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H,1′H-5,6′-bipyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 1-methyl-1H-pyrazolo[4,3-b]pyridin-6-ylboronic acidinstead of phenylboronic acid as starting material. LC-MS calculated forC₂₄H₂₅N₈ (M+H)⁺: m/z=425.2; found 425.2.

Example 29.2-(5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)oxazole

This compound was prepared according to the procedures described inExample 1, using 5-(oxazol-2-yl)pyridin-3-ylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₅H₂₄N₇O(M+H)⁺: m/z=438.2; found 438.2.

Example 30.1-Methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2(1H)-one

This compound was prepared according to the procedures described inExample 1, using 1-methyl-6-oxo-1,6-dihydropyridin-3-ylboronic acidinstead of phenylboronic acid as starting material. LC-MS calculated forC₂₃H₂₅N₆O (M+H)⁺: m/z=401.2; found 401.2.

Example 31.5-(3-Methyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 3-methyl-3H-imidazo[4,5-b]pyridin-6-ylboronic acidinstead of phenylboronic acid as starting material. LC-MS calculated forC₂₄H₂₅N₈ (M+H)⁺: m/z=425.2; found 425.2.

Example 32.7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyrido[3,2-b]pyrazine

This compound was prepared according to the procedures described inExample 1, using pyrido[3,2-b]pyrazin-7-ylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₄H₂₃N₈(M+H)⁺: m/z=423.2; found 423.2.

Example 33.2-tert-Butyl-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)oxazolo[5,4-c]pyridine

This compound was prepared according to the procedures described inExample 1, using 2-tert-butyloxazolo[5,4-c]pyridin-7-ylboronic acidinstead of phenylboronic acid as starting material. LC-MS calculated forC₂₇H₃₀N₇₀ (M+H)⁺: m/z=468.2; found 468.2.

Example 34.5-(3-Methyl-1H-pyrazol-4-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 3-methyl-1H-pyrazol-4-ylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₄H₂₄N₇(M+H)⁺: m/z=374.2; found 374.2. ¹H NMR (400 MHz, DMSO) δ 9.50 (d, J=2.2Hz, 1H), 8.82-8.72 (m, 2H), 8.55-8.45 (m, 2H), 8.24-8.09 (m, 2H),7.81-7.71 (dd, J=8.0, 5.0 Hz, 1H), 7.26-7.16 (m, 2H), 4.07-3.89 (m, 2H),3.65-3.47 (m, 2H), 3.30-3.03 (m, 4H), 2.95-2.80 (s, 3H).

Example 35.3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using pyrazolo[1,5-a]pyridin-3-ylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₄H₂₄N₇(M+H)⁺: m/z=410.2; found 410.2.

Example 36.5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)quinoline

This compound was prepared according to the procedures described inExample 1, using quinolin-5-ylboronic acid instead of phenylboronic acidas starting material. LC-MS calculated for C₂₆H₂₅N₆ (M+H)⁺: m/z=421.2;found 421.2.

Example 37.4-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)isoquinoline

This compound was prepared according to the procedures described inExample 1, using isoquinolin-4-ylboronic acid instead of phenylboronicacid as starting material. LC-MS calculated for C₂₆H₂₅N₆ (M+H)⁺:m/z=421.2; found 421.2.

Example 38.4-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)indolin-2-one

This compound was prepared according to the procedures described inExample 1, using 2-oxoindolin-4-ylboronic acid instead of phenylboronicacid as starting material. LC-MS calculated for C₂₅H₂₅N₆O (M+H)⁺:m/z=425.2; found 425.2.

Example 39.5-(1-Methyl-1H-indol-4-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 1, using 1-methyl-1H-indol-4-ylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₆H₂₇N₆(M+H)⁺: m/z=423.2; found 423.2.

Example 40.2-Fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzamide

Step 1. Ethyl2-fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-k]pyridin-5-yl)benzoate

To a solution of5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Example 1, Step 2, 200 mg, 0.61 mmol) in 1,4-dioxane (4 mL) and water(1 mL) was added ethyl2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (380mg, 1.29 mmol) and potassium phosphate (280 mg, 1.32 mmol), followed by(2′-aminobiphenyl-2-yl)(chloro)(dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene)palladium(50 mg, 0.064 mmol), and the reaction vial was purged with nitrogen for5 mins. After this time the reaction mixture was stirred at 90° C. for15 hours. It was then cooled to r.t., filtered and concentrated todryness. The residue was purified by silica gel chromatography using0-10% methanol in DCM to afford desired product as yellowish solid (151mg, 55%). LC-MS calculated for C₂₆H₂₇FN₅O₂ (M+H)⁺: m/z=460.2; found460.2.

Step 2.2-Fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzoicacid

To a solution of ethyl2-fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzoate(151 mg, 0.329 mmol) in methanol (4 mL) was added potassium hydroxide(185 mg, 3.30 mmol) and the reaction mixture was stirred at r.t. for 1hour. After this time the reaction was filtered and concentrated todryness. To the residue was added 1N HCl solution in water (10 mL) andthe product was extracted with ethyl acetate (2×10 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated to dryness to afford the crude desired product as yellowishsolid which was used for next step without purification. LC-MScalculated for C₂₄H₂₃FN₅O₂ (M+H)⁺: m/z=432.2; found 432.2.

Step 3.2-Fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzamide

To a solution of2-fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzoicacid (20 mg, 0.046 mmol) in N,N-dimethylformamide (1 mL) were addedammonia in dioxane (0.5 M in dioxane, 1 mL, 0.5 mmol),N,N-diisopropylethylamine (0.4 mL, 0.9 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (53 mg, 0.14 mmol). The reaction was stirred at r.t.for 30 mins, then diluted with acetonitrile, filtered and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).LC-MS calculated for C₂₄H₂₄FN₆O (M+H)⁺: m/z=431.2; found 431.2.

Example 41.2-Fluoro-N-methyl-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzamide

This compound was prepared according to the procedures described inexample 40, using methylamine solution instead of ammonia solution asstarting material. LC-MS calculated for C₂₅H₂₆FN₆₀ (M+H)⁺: m/z=445.2;found 445.2.

Example 42.N-Benzyl-2-fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)benzamide

This compound was prepared according to the procedures described inexample 40, using benzylamine instead of ammonia solution as startingmaterial. LC-MS calculated for C₃₁H₃₀FN₆O (M+H)⁺: m/z=521.2; found521.2.

Example 43.2-Fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-N-(pyridin-4-ylmethyl)benzamide

This compound was prepared according to the procedures described inExample 40, using pyridin-4-ylmethanamine instead of ammonia solution asstarting material. LC-MS calculated for C₃₀H₂₉FN₇O (M+H)⁺: m/z=522.2;found 522.2.

Example 44.5-(Imidazo[1,2-a]pyridin-8-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

Step 1.3-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2-amine

To a solution of5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Example 1, Step 2, 150 mg, 0.456 mmol) in 1,4-dioxane (4 mL) and water(1 mL) were added3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (100 mg,0.455 mmol), potassium phosphate (190 mg, 0.896 mmol) and(2′-aminobiphenyl-2-yl)(chloro)(dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene)palladium(40 mg, 0.051 mmol). The reaction was degassed and backfilled with N₂and stirred at 90° C. for 15 hours. The reaction mixture was cooled tor.t., diluted with ethyl acetate and washed with water and brine. Theorganic layer was dried over MgSO₄, filtered and concentrated todryness. The residue was used in the next step without purification.LC-MS calculated for C₂₂H₂₄N₇ (M+H)⁺: m/z=386.2; found 386.2.

Step 2.5-(Imidazo[1,2-a]pyridin-8-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2-amine(20 mg, 0.052 mmol) in isopropyl alcohol (1 mL) was addedN,N-diisopropylethylamine (20 mg, 0.16 mmol) and chloroacetaldehyde (40mg, 0.51 mmol) then it was stirred at 90° C. for 15 hours. After thistime the reaction mixture was cooled to r.t., diluted with methanol,filtered and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to afford desired product. LC-MS calculated for C₂₄H₂₄N₇ (M+H)⁺:m/z=410.2; found 410.2.

Example 45.5-(2-Ethylimidazo[1,2-a]pyridin-8-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 44, using 1-chlorobutan-2-one instead of chloroacetaldehyde asstarting material. LC-MS calculated for C₂₆H₂₈N₇ (M+H)⁺: m/z=438.2;found 438.2.

Example 46.5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1,2,3,4-tetrahydroisoquinoline

To a solution of5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Example 1, Step 2, 30 mg, 0.091 mmol) in 1,4-dioxane (1 mL) and water(0.25 mL) were added tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(66 mg, 0.18 mmol), potassium phosphate (39 mg, 0.18 mmol) and(2′-aminobiphenyl-2-yl)(chloro)(dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene)palladium(7 mg, 0.01 mmol). The reaction was degassed and backfilled with N₂ andstirred at 90° C. for 15 hours. The reaction mixture was cooled to r.t.,filtered and concentrated to dryness. 1 mL of 1:1 mixture of TFA and DCMwas added to the obtained residue and the reaction was stirred foranother 1 hour. The solution was concentrated to dryness, diluted withmethanol, filtered and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LC-MS calculated for C₂₆H₂₉N₆ (M+H)⁺:m/z=425.2; found 425.2.

Example 47.4-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

Step 1.4-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-one

To a solution of 4-bromoindan-1-one (200 mg, 0.952 mmol) in 1,4-dioxane(4 mL) were added bis(pinacolato)diboron (0.48 g, 1.9 mmol), potassiumacetate (0.19 g, 1.9 mmol) and(2′-aminobiphenyl-2-yl)(chloro)(dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene)palladium(100 mg, 0.127 mmol). The reaction was stirred at 100° C. for 4 hours.After this time it was cooled to r.t., and then water (0.8 mL),5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Example 1, Step 2, 200 mg, 0.608 mmol) and potassium phosphate (200 mg,0.943 mmol) were added and the reaction was stirred for another 4 hoursat 90° C. The reaction mixture was cooled to r.t., diluted with DCM (20mL) filtered and concentrated to dryness. The residue was used in thenext step without purification. LC-MS calculated for C₂₆H₂₆N₅O (M+H)⁺:m/z=424.2; found 424.2.

Step 2.4-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

To a solution of4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)indan-1-one(20 mg, 0.047 mmol) in methanol (20 mmol) was added ammonium acetate (40mg, 0.526 mmol) and sodium cyanoborohydride (10 mg, 0.16 mmol). Thereaction was stirred at 60° C. for 2 hours. After this time it wasdiluted with methanol, filtered and purified by prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LC-MS calculated for C₂₆H₂₉N₆ (M+H)⁺:m/z=425.2; found 425.2.

Example 48.N-Methyl-4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

To a solution of4-{3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-b]pyridin-5-yl}indan-1-one(Example 47, step 1, 20 mg, 0.047 mmol) in tetrahydrofuran (1 mL) wasadded sodium cyanoborohydride (10 mg, 0.16 mmol) and methyl amine (HClsalt, 30 mg, 0.44 mmol). The reaction was stirred at 80° C. for 4 hours.After this time it was cooled to r.t., diluted with methanol, filteredand purified by prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).LC-MS calculated for C₂₇H₃₁N₆ (M+H)⁺: m/z=439.2; found 439.2.

Example 49.2-(4-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-ylamino)ethanol

This compound was prepared according to the procedures described inexample 48, using 2-aminoethanol instead of methylamine as startingmaterial. LC-MS calculated for C₂₈H₃₃N₆O (M+H)⁺: m/z=469.2; found 469.2.

Example 50.N-Benzyl-4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-1-amine

This compound was prepared according to the procedures described inexample 48, using benzylamine instead of methylamine as startingmaterial. LC-MS calculated for C₃₃H₃₅N₆ (M+H)⁺: m/z=515.2; found 515.2.

Example 51. 5-(2-Fluorophenyl)-3-phenyl-1H-pyrazolo[4,3-b]pyridine

Step 1. 5-(2-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of 5-chloro-1H-pyrazolo[4,3-b]pyridine (500 mg, 3.29 mmol)in 1,4-dioxane (20 mL) and water (5 mL) were added(2-fluorophenyl)boronic acid (500 mg, 3.57 mmol), potassium phosphate(1.4 g, 6.5 mmol) and(2′-aminobiphenyl-2-yl)(chloro)(dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene)palladium(100 mg, 0.127 mmol). The reaction was degassed and backfilled with N₂and stirred at 90° C. for 15 hours. After this time it was cooled tor.t., filtered and concentrated to dryness. The residue was purified bysilica gel chromatography using 0-100% ethyl acetate in hexanes toafford desired product as yellowish oil (620 mg, 98%). LC-MS calculatedfor C₁₂H₉FN₃ (M+H)⁺: m/z=214.2; found 214.2.

Step 2. 5-(2-Fluorophenyl)-3-iodo-1H-pyrazolo[4,3-b]pyridine

To a solution of 5-(2-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (750 mg,3.50 mmol) in 1,4-dioxane (20 mL) were added iodine (1.8 g, 7.0 mmol)and potassium hydroxide (590 mg, 10.5 mmol) and the reaction was stirredat 50° C. for 15 hours. The resulting slurry was poured into an aq.solution of sodium thiosulfate and stirred for 15 mins. After this timethe product was extracted with ethyl acetate. The organic layer waswashed with brine, dried with MgSO₄, filtered and concentrated todryness to afford the crude product as brownish solid which was used inthe next step without purification. LC-MS calculated for C₁₂H₈FIN₃(M+H)⁺: m/z=340.2; found 340.2.

Step 3. 5-(2-Fluorophenyl)-3-phenyl-1H-pyrazolo[4,3-b]pyridine

To a solution of 5-(3-fluorophenyl)-3-iodo-1H-pyrazolo[4,3-b]pyridine(30 mg, 0.09 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL) were addedphenylboronic acid (16 mg, 0.13 mmol), potassium phosphate (38 mg, 0.18mmol) and(2′-aminobiphenyl-2-yl)(chloro)(dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene)palladium(20 mg, 0.013 mmol). The reaction was degassed and stirred at 100° C.for 3 hours. The reaction mixture was then cooled to r.t., diluted withmethanol, filtered and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LC-MS calculated for C₁₈H₁₃FN₃ (M+H)⁺:m/z=290.2; found 290.2.

Example 52.5-(2-Fluorophenyl)-3-(pyridin-4-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 51, using pyridin-4-ylboronic acid instead of phenylboronic acidas starting material. LC-MS calculated for C₁₇H₁₂FN₄ (M+H)⁺: m/z=291.2;found 291.2.

Example 53.4-(5-(2-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-N-methylbenzamide

This compound was prepared according to the procedures described inExample 51, using 4-(methylcarbamoyl)phenylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₂₀H₁₆FN₄O(M+H)⁺: m/z=347.2; found 347.2.

Example 54.5-(2-Fluorophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

This compound was prepared according to the procedures described inExample 51, using 1-methyl-1H-pyrazol-4-ylboronic acid instead ofphenylboronic acid as starting material. LC-MS calculated for C₁₆H₁₃FN₅(M+H)⁺: m/z=294.2; found 294.2.

Example 55.4-(5-(2-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-N-(1-methylpiperidin-4-yl)benzamide

Step 1. 4-(5-(2-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)benzoicacid

To a solution of 5-(3-fluorophenyl)-3-iodo-1H-pyrazolo[4,3-b]pyridine(Example 51, Step 2, 300 mg, 0.882 mmol) in 1,4-dioxane (10 mL) andwater (2 mL) were added (4-(methoxycarbonyl)phenyl)boronic acid (240 mg,1.33 mmol), potassium phosphate (380 mg, 1.79 mmol) and(2′-aminobiphenyl-2-yl)(chloro)(dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene)palladium(70 mg, 0.089 mmol). The reaction was degassed and stirred at 100° C.for 15 hours. The reaction mixture was cooled to r.t., filtered andconcentrated to dryness. The residue was dissolved in methanol (10 mL)and potassium hydroxide (500 mg, 8.93 mmol) was added. The reaction wasstirred at r.t. for 1 hour. After this time the reaction mixture wasconcentrated to dryness, diluted with water, acidified with 1N HCl andthe product extracted with ethyl acetate. The organic layer was driedover MgSO₄, filtered and concentrated to dryness to afford a crudeproduct as white solid. It was used in the next step without furtherpurification. LC-MS calculated for C₁₉H₁₃FN₃O₂ (M+H)⁺: m/z=334.2; found334.2.

Step 2.4-(5-(2-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-N-(1-methylpiperidin-4-yl)benzamide

To a solution of4-(5-(2-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)benzoic acid (30mg, 0.090 mmol) in N,N-dimethylformamide (1 mL) were addedN,N-diisopropylethylamine (40 mg, 0.31 mmol), 1-methylpiperidin-4-amine(50 mg, 0.44 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU, 100 mg, 0.263 mmol). The reaction was stirredfor 30 mins at r.t., then it was diluted with methanol, filtered andpurified by prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).LC-MS calculated for C₂₅H₂₅FN₅O (M+H)⁺: m/z=430.2; found 430.2.

Example 56.(4-(5-(2-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)(4-methylpiperazin-1-yl)methanone

This compound was prepared according to the procedures described inExample 55, using 1-methylpiperazine instead of1-methylpiperidin-4-amine as starting material. LC-MS calculated forC₂₄H₂₃FN₅O (M+H)⁺: m/z=416.2; found 416.2.

Example 57.4-(5-(2-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-N-phenylbenzamide

This compound was prepared according to the procedures described inExample 55, using aniline instead of 1-methylpiperidin-4-amine asstarting material. LC-MS calculated for C₂₅H₁₈FN₄O (M+H)⁺: m/z=409.2;found 409.2.

Example 58.5-(2-Fluorophenyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

To a solution of 5-(3-fluorophenyl)-3-iodo-1H-pyrazolo[4,3-b]pyridine(30 mg, 0.090 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL) were added(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid(39 mg, 0.13 mmol), potassium phosphate (38 mg, 0.18 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg,0.027 mmol). The reaction was degassed and was stirred at 100° C. for 3hours. The reaction mixture was then cooled to r.t., filtered andconcentrated to dryness. It was dissolved in dioxane (1 mL) and 1N HClsolution in water was added. The reaction mixture was stirred at r.t.for 1 hour. After this time the solution was diluted with methanol,filtered and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LC-MS calculated for C₂₀H₂₀FN₆ (M+H)⁺: m/z=363.2; found 363.2.

Example 59.5-(2-Fluorophenyl)-3-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-(2-fluorophenyl)-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine(20 mg, 0.055 mmol) in 1,4-dioxane (1 mL) were addedN,N-diisopropylethylamine (20 mg, 0.16 mmol) and methanesulfonylchloride (20 mg, 0.18 mmol). The reaction was stirred at r.t. for 1hour. The resulting solution was diluted with methanol, filtered andpurified by prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).LC-MS calculated for C₂₁H₂₂FN₆O₂S (M+H)⁺: m/z=441.2; found 441.2.

Example 60.1-(4-(4-(5-(2-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone

This compound was prepared according to the procedures described inExample 59, using acetyl chloride instead of methanesulfonyl chloride asstarting material. LC-MS calculated for C₂₂H₂₂FN₆O (M+H)⁺: m/z=405.2;found 405.2.

Intermediate 1.5-Chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

Step 1.5-Chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of 5-chloro-1H-pyrazolo[4,3-b]pyridine (1.0 g, 6.5 mmol)in acetonitrile (32.6 ml) was added N-iodosuccinimide (1.61 g, 7.16mmol) and the reaction mixture was stirred at 50° C. for 2 hours. Thereaction mixture was cooled to room temperature and DIPEA (1.25 ml, 7.16mmol) was added followed by the addition of SEM-Cl (1.27 ml, 7.16 mmol).The resulting solution was stirred for another 1 hour at roomtemperature and then concentrated to dryness. The residue was purifiedby silica gel chromatography using 0-100% ethyl acetate in hexanes toafford desired product as yellowish solid (2.2 g, 82%). LC-MS calculatedfor C₁₂H₈ClIN₃OSi (M+H)⁺: m/z=410.0; found 410.0.

Step 2.5-Chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of5-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-b]pyridine(2.2 g, 5.4 mmol) in dioxane (43.0 ml) and water (10.7 ml) was addedpotassium phosphate (2.28 g, 10.7 mmol),1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine(1.623 g, 5.37 mmol) followed by Pd-dppf (4.38 g, 5.37 mmol). Thereaction mixture was degassed by bubbling nitrogen through the mixturefor 10 minutes and was then stirred at 90° C. for 15 hours. Aftercooling to room temperature it was concentrated to dryness. The residuewas purified by silica gel chromatography using 0-10% methanol in DCM toafford Intermediate 1 as brownish oil (1.8 g, 73%). LC-MS calculated forC₂₃H₃₃ClN₅OSi (M+H)⁺: m/z=458.0; found 458.0.

Intermediate 2. tert-Butyl3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamate

Step 1. 4-Bromo-3-fluoro-5-methylaniline

N-Bromosuccinimide (15.8 g, 89 mmol) was added to a solution of3-fluoro-5-methylaniline (Combi-Blocks, 11 g, 88 mmol) in DMF (80 mL)cooled to 0° C. in an ice bath. The reaction mixture was stirred at 0°C. for 30 minutes. After warming to room temperature, the reaction wasstirred for an additional 1 hour. Water and EtOAc were then added, andthe separated organic phase was washed with saturated aqueous NaHCO₃ andbrine. The organic phase was dried over magnesium sulfate andconcentrated under reduced pressure. The crude product was purified byBiotage Isolera™ (17.2 g, 96%). LCMS calculated for C₇H₈BrFN (M+H)⁺m/z=203.9; found 204.0.

Step 2. 2-Bromo-1-fluoro-5-iodo-3-methylbenzene

To a solution of 4-bromo-3-fluoro-5-methylaniline (7.28 g, 36 mmol) inacetonitrile (190 mL) cooled to 0° C. was added aqueous sulfuric acid(4.75 mL, 89 mmol in 10 mL H₂O). After stirring for 5 minutes, asolution of sodium nitrite (4.92 g, 71.4 mmol) in water (10 mL) wasadded dropwise and the reaction mixture was stirred for an additional 15minutes at 0° C. Potassium iodide (23.7 g, 143 mmol) in water (20 mL)was then added, and the ice-bath was removed. After warming to roomtemperature the reaction was stirred for an additional 20 minutes beforethe reaction was treated with aqueous Na₂S₂O₃. The mixture was extractedwith ethyl acetate and the combined organic phases were washed withbrine, dried over magnesium sulfate, and concentrated under reducedpressure. The crude product was purified by Biotage Isolera™ (10.3 g,94%). ¹H NMR (400 MHz, CDCl₃) δ 7.39 (br s, 1H), 7.29 (m, 1H), 2.38 (s,3H) ppm.

Step 3. 2-Bromo-1-fluoro-3-methyl-5-vinylbenzene

To a solution of 2-bromo-1-fluoro-5-iodo-3-methylbenzene (10.3 g, 32.8mmol) in 1,4-dioxane (80 mL) and water (13.3 mL) was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich, 6.16 mL, 34.5mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)(Pd(dppf)Cl₂) (2.40 g, 3.3 mmol), and potassium phosphate tribasic (13.9g, 65.7 mmol). The reaction mixture was degassed by bubbling nitrogenthrough the mixture for 10 minutes and then heated to 70° C. for 1 h.After cooling to room temperature the reaction mixture was filtered overa pad of Celite, diluted with water, and extracted with ethyl acetate.The combined organic phases were washed with brine, dried over magnesiumsulfate, and concentrated under reduced pressure. The crude product waspurified by Biotage Isolera™ (5.46 g, 77%). ¹H NMR (400 MHz, CDCl₃) δ7.05 (br s, 1H), 7.01 (dd, J=2.0, 9.4 Hz, 1H), 6.60 (dd, J=10.9, 17.5Hz, 1H), 5.75 (d, J=17.5 Hz, 1H), 5.31 (d, J=10.9 Hz, 1H), 2.42 (s, 3H)ppm.

Step 4. 4-Bromo-3-fluoro-5-methylbenzaldehyde

To a solution of 2-bromo-1-fluoro-3-methyl-5-vinylbenzene (5.46 g, 25.4mmol) in acetone (46 mL) and water (4.6 mL) was sequentially addedsodium periodate (21.7 g, 102 mmol) and a 4% aqueous solution of osmiumtetroxide (8.07 mL, 1.27 mmol). The reaction was stirred at r.t. for 2h. The reaction mixture was then filtered over a pad of celite, dilutedwith water, and extracted with ethyl acetate. The combined organicphases were washed with brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The crude product was purified byBiotage Isolera™ (3.22 g, 58%). ¹H NMR (400 MHz, CDCl₃) δ 9.93 (d, J=1.8Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.44 (dd, J=1.8, 7.8 Hz, 1H), 2.52 (s,3H) ppm.

Step 5. 1-(4-Bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine

In a 20 mL scintillation vial equipped with a magnetic stir bar,4-bromo-3-fluoro-5-methylbenzaldehyde (1.46 g, 6.70 mmol) was dissolvedin MeOH (6.70 mL) and the solution was placed under a nitrogenenvironment. A 33% solution of methanamine (3.15 g, 33.5 mmol) inethanol and titanium(IV) isopropoxide (0.982 mL, 3.35 mmol) were addedand the reaction mixture was stirred at room temperature for 3 hours.Sodium borohydride (1.01 g, 26.8 mmol) was then added to the reactionmixture portion wise and stirring was continued at room temperature foran additional 1.5 hours. The reaction mixture was treated with NH₄OH(30% aqueous solution) and stirring continued for another 15 minutes.The reaction was then acidified with 1 N HCl and extracted with ethylacetate. The separated aqueous phase was then made basic and extractedwith ethyl acetate. The combined organic phases were washed with brine,dried over magnesium sulfate, and concentrated under reduced pressure toafford 1-(4-bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine (1.32 g,85%) as a light yellow oil. The crude product was used in the next stepwithout further purification. LCMS calculated for C₉H₁₂BrFN (M+H)⁺m/z=232.0; found 231.9.

Step 6. tert-Butyl 4-bromo-3-fluoro-5-methylbenzyl(methyl)carbamate

To a solution of 1-(4-bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine(1.32 g, 5.67 mmol) and triethylamine (1.58 mL, 11.34 mmol) in THF (18.9mL) was added di-tert-butyl dicarbonate (1.58 mL, 6.80 mmol). Thereaction mixture was stirred at ambient temperature for 1 hour. Thereaction mixture was then diluted with water and extracted with ethylacetate. The combined organic phases were dried with magnesium sulfateand concentrated under reduced pressure. The crude product was purifiedby Biotage Isolera™ (1.42 g, 78%). LCMS calculated for C₁₀H₁₂BrFNO₂(M+H-C₄H₈)⁺ m/z=276.0; found 276.0.

Step 7. tert-Butyl3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamate

In an 20 mL scintillation vial, tert-butyl(4-bromo-3-fluoro-5-methylbenzyl)(methyl)-carbamate (573 mg, 1.73 mmol)was dissolved in THF (11.5 mL). The solution was then cooled to −78° C.and n-BuLi (1.6 M solution in hexanes, 1.19 mL, 1.90 mmol) was addeddropwise. The reaction mixture was then allowed to stir for 3 minutesbefore 2-isopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (427 μL, 2.25mmol) was added dropwise. The mixture was warmed to room temperature andstirred for an additional 5 hours. The reaction was then treated withwater, acidified to pH 5-6 using 1 N HCl, and extracted with ethylacetate. The combined organic phases were washed with brine, dried overmagnesium sulfate, and concentrated to afford tert-butyl3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)-carbamate.The crude product was used in the next step without furtherpurification. LCMS calculated for C₁₆H₂₄BrFNO₄ (M+H−C₄H₈)⁺ m/z=324.2;found 324.1.

Example 61.1-(3,5-Difluoro-4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)-N-methylmethanamine

Step 1. tert-Butyl 3,5-difluorobenzyl(methyl)carbamate

To a solution of 3,5-difluorobenzaldehyde (15.0 g, 106 mmol) in methanol(528 ml) was added 2M solution of methylamine in THF (79.0 ml, 158 mmol)and the reaction mixture was stirred at room temperature for 1 hour.Then sodium borohydride (7.99 g, 211 mmol) was added and the reactionmixture was stirred at room temperature until gas evolution had stopped.The solvents were evaporated in vacuo and residue was dissolved in 300mL of DCM. Sodium bicarbonate solution was added and the reactionmixture was stirred at room temperature for 1 hour. The organic phasewas separated, dried over MgSO₄, filtered and concentrated to dryness.To a solution of the resulting residue in DCM (528 ml) was added DIPEA(18.4 ml, 106 mmol) and di-tert-butyl dicarbonate (24.51 ml, 106 mmol).The mixture was stirred at room temperature for 1 hour, concentrated invacuo to dryness and the residue purified by silica gel chromatographyusing 0-70% ethyl acetate in hexanes. The desired product was isolatedas a colorless oil (15.0 g, 55.4%). LC-MS calculated for C₁₃H₁₈F₂NO₂(M+H)⁺: m/z=258.2; found 258.2.

Step 2.1-(3,5-Difluoro-4-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)phenyl)-N-methylmethanamine

To a solution of tert-butyl (3,5-difluorobenzyl)(methyl)carbamate (0.500g, 1.94 mmol) in THF (8.6 ml) under nitrogen was added 2.5M solution ofn-butyllithium in hexane (0.933 ml, 2.33 mmol) dropwise at −78° C. Thereaction mixture was stirred at that temperature for 1 hour. Then2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.542 g, 2.92mmol) was added and the reaction mixture was allowed to warm to roomtemperature over 1 hour. The resulting mixture was treated with waterand extracted with ethyl acetate. The combined organic phases werewashed with brine, dried over MgSO₄, filtered and concentrated todryness. To a solution of the resulting residue in dioxane (8.64 ml) andwater (2.159 ml) was added intermediate 1 (0.089 g, 0.19 mmol) andpotassium phosphate, tribasic (0.338 g, 1.94 mmol). The reaction mixturewas degassed by bubbling nitrogen through the mixture for 10 minutes andthenchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (0.076 g, 0.097 mmol) was added. The reaction mixture wasstirred at 60° C. for 1 hour followed by addition of 5 mL of 4N HCl indioxane and 4 mL of water. The resulting mixture was stirred at 80° C.for 2 hours, cooled to room temperature, diluted with acetonitrile,filtered and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LC-MS calculated for C₂₅H₂₇F₂N₆ (M+H)⁺: m/z=449.2; found 449.2.

Example 62.5-(2-Fluoro-6-methylphenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

Step 1. 6-Bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine

To a suspension of NaH (60% in mineral oil, 755.4 mg, 18.89 mmol) in DMF(20.0 mL) at 0° C. was added a solution of6-bromo-1H-pyrazolo[4,3-b]pyridine (2.469 g, 12.47 mmol) in DMF (20.0mL) dropwise. The mixture was allowed to warm to room temperature andstirred for 30 min. The reaction mixture was cooled back to 0° C. beforea solution of (chloromethanetriyl)-tribenzene (4.20 g, 15.07 mmol) inDMF (20.0 mL) was added dropwise. The reaction mixture was allowed towarm to room temperature and was stirred for 16 h. The reaction mixturewas treated with sat. NH₄Cl(aq) and extracted with DCM. The combinedorganic phases were concentrated and the residue was purified on silicagel (120 g, 0-50% EtOAc in hexanes) to give the desired product as awhite solid (4.80 g, 87%). LCMS calculated for C₂₅H₁₉BrN₃ (M+H)⁺:m/z=440.1; found 440.0.

Step 2. 6-Bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide

To a solution of 6-bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine (3.240 g,7.36 mmol) in DCM (60.0 ml) was added m-CPBA (5.83 g, 26.0 mmol)portionwise. After stirring at room temperature for 16 h, the reactionmixture was treated with a solution of sodium thiosulfate (30.0 g, 190mmol) in water (100 ml). The organic phase was washed with 2 M K₂CO₃(aq), dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified on silica gel (120 g, 0-100% EtOAc in DCM) to givethe desired product as a white foamy solid (3.22 g, 96%). LCMScalculated for C₂₅H₁₉BrN₃O (M+H)⁺: m/z=456.1; found 456.0.

Step 3. 6-Cyano-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide

A vial was charged with 6-bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine4-oxide (1.623 g, 3.56 mmol), dicyanozinc (1.691 g, 14.40 mmol),tris(dibenzylideneacetone)dipalladium(0) (376.8 mg, 0.411 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (455.4 mg, 0.787 mmol).The vial was sealed, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of TMEDA (341.5mg, 2.94 mmol) in DMF (15.0 ml) was added. The reaction mixture wasstirred at 110° C. for 2 h. After cooling to room temperature, thereaction mixture was filtered. The filter cake was washed with DCM. Thefiltrate was concentrated. The resultant residue was purified on silicagel (120 g, 0-100% EtOAc in DCM) to give the desired product as a yellowfoamy solid (894.5 mg, 63%). LCMS calculated for C₂₆H₁₈N₄NaO (M+Na)⁺:m/z=425.1; found 425.1.

Step 4. 5-Chloro-1-trityl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

To a solution of 6-cyano-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide(447.3 mg, 1.1 mmol) in DCM (10.0 ml) at 0° C. was added Et₃N (264.9 mg,2.62 mmol) followed by the dropwise addition of a solution of oxalylchloride (317.6 mg, 2.5 mmol) in DCM (3.0 ml). After stirring at 0° C.for 30 min, the mixture was diluted with DCM and washed with sat.NaHCO₃. The organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes) to give the desired product as a white foamy solid (446.7mg, 95%). LCMS calculated for C₂₆H₁₇ClN₄Na (M+Na)⁺: m/z=443.1; found443.1.

Step 5.5-(2-Fluoro-6-methylphenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

A screw-cap vial was charged with5-chloro-1-trityl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile (362.4 mg,0.861 mmol),chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(SPhos Pd G2, 57.8 mg, 0.080 mmol) and cesium carbonate (869.3 mg, 2.67mmol). The vial was sealed, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of(2-fluoro-6-methylphenyl)boronic acid (184.5 mg, 1.2 mmol) in1,4-dioxane (10.0 ml) was added, followed by water (2.0 ml). Thereaction mixture was stirred at 50° C. for 16 h. The reaction mixturewas concentrated. The resultant residue was purified on silica gel (40g, 0-100% EtOAc in hexanes) to give the desired product as a pale yellowsolid (406.1 mg, 95%). LCMS calculated for C₃₃H₂₄FN₄ (M+H)⁺: m/z=495.2;found 495.2.

Step 6.5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

To a solution of5-(2-fluoro-6-methylphenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile(406.1 mg, 0.821 mmol) in DCM (10.0 ml) was added TFA (5.0 ml). Thereaction was stirred at room temperature for 30 min, and thenconcentrated. The residue was dissolved in DCM and washed with sat.NaHCO₃(aq). The organic phase was dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was purified on silica gel (40 g, 0-100%EtOAc in DCM) to give the desired product as a white solid (140.1 mg,68%). LCMS calculated for C₁₄H₁₀FN₄ (M+H)⁺: m/z=253.1; found 253.1.

Step 7. tert-Butyl6-cyano-5-(2-fluoro-6-methylphenyl)-3-iodo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

To a solution of5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile(140.1 mg, 0.555 mmol) in DMF (8.0 ml) was added N-iodosuccinimide(175.2 mg, 0.779 mmol). The mixture was stirred at 80° C. for 2 h. Aftercooling to room temperature, Boc-anhydride (168.1 mg, 0.770 mmol) wasadded followed by DMAP (24.9 mg, 0.204 mmol). The reaction was stirredat room temperature for 30 min, and then concentrated. The residue waspurified on silica gel (40 g, 0-100% EtOAc in hexanes) to give thedesired product as a white foamy solid (244.3 mg, 92%). LCMS calculatedfor C₁₉H₁₇FIN₄O₂ (M+H)⁺: m/z=479.0; found 479.0.

Step 8.5-(2-Fluoro-6-methylphenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

A vial was charged with1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(20.4 mg, 0.067 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 5.3 mg, 6.74 μmol) and cesium carbonate (53.3 mg, 0.164mmol). The vial was sealed, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of tert-butyl6-cyano-5-(2-fluoro-6-methylphenyl)-3-iodo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(20.0 mg, 0.042 mmol) in 1,4-dioxane (2.00 ml) was added, followed bywater (200.0 μL). The reaction mixture was heated to 50° C. for 16 h.The reaction mixture was concentrated. To the resultant residue wasadded CH₂Cl₂ (2.0 mL) followed by TFA (2.0 mL). The mixture was stirredat room temperature for 15 min, and then concentrated. The residue waspurified using prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₄H₂₃FN₇ (M+H)⁺:m/z=428.2; found: 428.2.

Example 63.5-(2-Fluoro-6-methylphenyl)-3-(2-morpholinopyrimidin-5-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

This compound was prepared according to the procedure described inExample 62, using4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholineinstead of1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₂H₁₉FN₇O (M+H)⁺:m/z=416.2; found: 416.1. ¹H NMR (TFA salt, 400 MHz, DMSO) δ 14.18 (br,1H), 9.23 (s, 2H), 8.94 (s, 1H), 7.55-7.44 (m, 1H), 7.28 (d, J=7.7 Hz,1H), 7.23 (t, J=8.9 Hz, 1H), 3.81-3.72 (m, 4H), 3.69-3.62 (m, 4H), 2.14(s, 3H).

Example 64.3-(4-(4-Ethylpiperazin-1-yl)phenyl)-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

This compound was prepared according to the procedure described inExample 62, using1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazineinstead of1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₆H₂₆FN₆ (M+H)⁺:m/z=441.2; found: 441.2.

Example 65.5-(6-Cyano-5-(2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-N-methylpicolinamide

This compound was prepared according to the procedure described inExample 62, usingN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamideinstead of1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₁H₁₆FN₆O (M+H)⁺:m/z=387.1; found: 387.1.

Example 66.5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

Step 1. tert-Butyl4-(6-cyano-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-fluoro-5-methylbenzyl(methyl)carbamate

A vial was charged with5-chloro-1-trityl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile (see step 4in example 62, 449.7 mg, 1.068 mmol),bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine)dichloropalladium(II)(76.2 mg, 0.108 mmol) and CsF (668.8 mg, 4.40 mmol). The vial wassealed, evacuated and backfilled with nitrogen (this process wasrepeated a total of three times). A solution of tert-butyl(3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate(Intermediate 2, 557.8 mg, 1.471 mmol) in butan-1-ol (9.00 ml) wasadded, followed by water (3.00 ml). After stirring at 60° C. for 90 min,the reaction mixture was concentrated. The residue was purified onsilica gel (40 g, 0-100% EtOAc in hexanes) to give the desired productas a yellow semi-solid (585.9 mg, 86%). LCMS calculated for C₄₀H₃₇FN₅O₂(M+H)⁺: m/z=638.3; found: 638.3.

Step 2. tert-Butyl4-(6-cyano-1H-pyrazolo[4,3-h]pyridin-5-yl)-3-fluoro-5-methylbenzyl(methyl)carbamate

To a solution of tert-butyl(4-(6-cyano-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-fluoro-5-methylbenzyl)(methyl)carbamate(585.9 mg, 0.919 mmol) in DCM (10.0 ml) was added TFA (5.0 ml). Thereaction was stirred at room temperature for 30 min, and thenconcentrated. The residue was dissolved in DCM and washed with sat.NaHCO₃(aq). The organic phase was dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was dissolved in DCM (10.0 ml), andtreated with a solution of Boc-anhydride (199.1 mg, 0.912 mmol) in DCM(10.0 ml). The mixture was stirred at room temperature for 15 min, andconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes) to give the desired product as a yellow foamy solid (252.3mg, 69%). LCMS calculated for C₂₁H₂₂FN₅NaO₂ (M+Na)⁺: m/z=418.2; found:418.2.

Step 3. tert-Butyl5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-6-cyano-3-iodo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

To a solution of tert-butyl(4-(6-cyano-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-fluoro-5-methylbenzyl)(methyl)carbamate(252.3 mg, 0.638 mmol) in DMF (6.0 ml) was added N-iodosuccinimide(201.2 mg, 0.894 mmol). The mixture was stirred at 80° C. for 2 h. Aftercooling to room temperature, Boc-anhydride (208.6 mg, 0.956 mmol) wasadded followed by DMAP (28.5 mg, 0.233 mmol). The reaction mixture wasstirred at room temperature for 30 min, and then concentrated. Theresidue was purified on silica gel (40 g, 0-100% EtOAc in hexanes) togive the desired product as a yellow foamy solid (269.3 mg, 68%). LCMScalculated for C₂₆H₃₀FIN₅O₄ (M+H)⁺: m/z=622.1; found: 622.1.

Step 4.5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

A vial was charged with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(11.0 mg, 0.053 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 4.8 mg, 6.10 μmol) and cesium carbonate (33.2 mg, 0.102mmol). The vial was sealed, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of tert-butyl5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-6-cyano-3-iodo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate(18.1 mg, 0.029 mmol) in 1,4-dioxane (2.00 ml) was added, followed bywater (200.0 μl). The reaction mixture was heated to 50° C. for 16 h.The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0 mL)followed by TFA (2.0 mL). The mixture was stirred at room temperaturefor 15 min, and then concentrated. The resultant residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₀H₁₉FN₇ (M+H)⁺:m/z=376.2; found: 376.2.

Example 67.5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

This compound was prepared according to the procedure described inExample 66, using1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asthe starting material. LCMS calculated for C₂₆H₂₈FN₈ (M+H)⁺: m/z=471.2;found: 471.1.

Example 68.5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

This compound was prepared according to the procedure described inExample 66, using2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidineinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asthe starting material. LCMS calculated for C₂₅H₂₇FN₉ (M+H)⁺: m/z=472.2;found: 472.2.

Example 69.3-(4-(4-Ethylpiperazin-1-yl)phenyl)-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

This compound was prepared according to the procedure described inExample 66, using1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazineinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asthe starting material. LCMS calculated for C₂₈H₃₁FN₇ (M+H)⁺: m/z=484.3;found: 484.2.

Example 70.5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(2-morpholinopyrimidin-5-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

This compound was prepared according to the procedure described inExample 66, using4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)morpholineinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asthe starting material. LCMS calculated for C₂₄H₂₄FN₈₀ (M+H)⁺: m/z=459.2;found: 459.1.

Example 71.5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

This compound was prepared according to the procedure described inExample 66, using2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propan-2-olinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asthe starting material. LCMS calculated for C₂₄H₂₄FN₆O (M+H)⁺: m/z=431.2;found: 431.1.

Example 72.5-(6-Cyano-5-(2-fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-N-methylpicolinamide

This compound was prepared according to the procedure described inExample 66, usingN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamideinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asthe starting material. LCMS calculated for C₂₃H₂₁FN₇O (M+H)⁺: m/z=430.2;found: 430.1. ¹H NMR (TFA salt, 400 MHz, DMSO) δ 14.62 (br, 1H), 9.57(m, 1H), 9.06 (s, 1H), 8.95 (br, 2H), 8.84 (dd, J=8.2, 2.1 Hz, 1H),8.83-8.77 (m, 1H), 8.17 (d, J=8.2 Hz, 1H), 7.41 (m, 2H), 4.23 (t, J=5.1Hz, 2H), 2.83 (d, J=4.8 Hz, 3H), 2.65 (t, J=4.8 Hz, 3H), 2.20 (s, 3H).

Example 73.5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-3-(pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

This compound was prepared according to the procedure described inExample 66, using3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asthe starting material. LCMS calculated for C₂₁H₁₈FN₆ (M+H)⁺: m/z=373.2;found: 373.1.

Example 74.5-(6-Fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

Step 1. 5-Bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline

To a solution of 5-bromo-6-fluoroisoquinoline (1.0 g, 4.4 mmol) inacetic acid (20.0 mL) at room temperature was added sodiumtetrahydroborate (592.0 mg, 15.65 mmol) portionwise. The mixture wasstirred at room temperature for 16 h, and then concentrated. The residuewas diluted with CH₂Cl₂ and washed with aqueous Na₂CO₃ (2 M). Theseparated organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated to give a yellow oil which was used directly in the nextstep without further purification. LCMS calculated for C₉H₁₀BrFN (M+H)⁺m/z=230.0; found 230.1.

Step 2. tert-Butyl5-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of 5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline (1.0 g,4.3 mmol) in CH₂Cl₂ (12.0 mL) was added di-tert-butyl dicarbonate (1.617g, 7.409 mmol). The mixture was stirred at room temperature for 1 h, andthen concentrated. The residue was purified on silica gel (120 g, 0-100%EtOAc in hexanes) to give the desired product as a white solid (1.119 g,76% over two steps). LCMS calculated for C₁₄H₁₇BrFNNaO₂ (M+Na)⁺m/z=352.0; found 352.0.

Step 3. tert-Butyl6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

A vial was charged with tert-butyl5-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.119 g,3.389 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](1.358 g,5.348 mmol), potassium acetate (1.101 g, 11.22 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexedwith dichloromethane (1:1) (298.6 mg, 0.366 mmol). The vial was sealed,evacuated and backfilled with nitrogen (this process was repeated atotal of three times). 1,4-Dioxane (15.0 mL) was added and the mixturewas heated at 100° C. for 16 h. After cooling to room temperature, thereaction mixture was diluted with CH₂Cl₂ and filtered. The filtrate wasconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes) to give the desired product as a pale yellow oil (1001 mg,78%). LCMS calculated for C₂₀H₂₉BFNNaO₄ (M+Na)⁺ m/z=400.2; found 400.2.

Step 4. tert-Butyl5-(6-cyano-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-yl)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

A vial was charged with5-chloro-1-trityl-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile (see step 4in example 62, 569.3 mg, 1.353 mmol),bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine)dichloropalladium(II)(99.8 mg, 0.141 mmol) and CsF (822.2 mg, 5.41 mmol). A solution oftert-butyl6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(666.7 mg, 1.767 mmol) in butan-1-ol (9.00 ml) was added, followed bywater (3.00 ml). After stirring at 60° C. for 3 h, the reaction wasconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes) to give the desired product (860 mg). LCMS calculated forC₄₀H₃₄FN₅NaO₂ (M+Na)⁺: m/z=658.3; found: 658.2.

Step 5. tert-Butyl5-(6-cyano-1H-pyrazolo[4,3-b]pyridin-5-yl)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of tert-butyl5-(6-cyano-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-yl)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(860 mg, 1.353 mmol) in DCM (10.0 ml) was added TFA (6.0 ml). Thereaction was stirred at room temperature for 30 min, and thenconcentrated. The residue was dissolved in DCM, washed with sat.NaHCO₃(aq). The aqueous phase was extracted with DCM (10×). The combinedorganic phases were dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was dissolved in DCM (10.0 ml) and treatedwith a solution of Boc-anhydride (300.0 mg, 1.375 mmol) in DCM (10.0ml). The mixture was stirred at room temperature for 15 min andconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes) to give the desired product as a yellow foamy solid (354.7mg, 67%). LCMS calculated for C₂₁H₂₀FN₅NaO₂ (M+Na)⁺: m/z=416.1; found:416.1.

Step 6. tert-Butyl5-(1-(tert-butoxycarbonyl)-6-cyano-3-iodo-1H-pyrazolo[4,3-b]pyridin-5-yl)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of tert-butyl5-(6-cyano-1H-pyrazolo[4,3-b]pyridin-5-yl)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(354.7 mg, 0.902 mmol) in DMF (6.0 ml) was added N-iodosuccinimide(304.2 mg, 1.352 mmol). The mixture was stirred at 80° C. for 2 h, andcooled to room temperature. Boc-anhydride (306.1 mg, 1.403 mmol) wasadded, followed by DMAP (31.6 mg, 0.259 mmol). The reaction was stirredat room temperature for 30 min, and then concentrated. The residue waspurified on silica gel (40 g, 0-100% EtOAc in hexanes) to give thedesired product as a yellow foamy solid (407.4 mg, 73%). LCMS calculatedfor C₂₆H₂₇FIN₅NaO₄ (M+Na)⁺: m/z=642.1; found: 642.0.

Step 7.5-(6-Fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

A vial was charged with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(11.2 mg, 0.054 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 4.5 mg, 5.72 μmop and cesium carbonate (38.3 mg, 0.118mmol). The vial was sealed, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of tert-butyl5-(1-(tert-butoxycarbonyl)-6-cyano-3-iodo-1H-pyrazolo[4,3-b]pyridin-5-yl)-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(20.0 mg, 0.032 mmol) in 1,4-dioxane (2.00 ml) was added, followed bywater (200.0 μl). The reaction mixture was heated to 50° C. for 16 h.The reaction mixture was concentrated. The residue was dissolved inCH₂Cl₂ (2.0 mL) and treated with TFA (2.0 mL). The mixture was stirredat room temperature for 15 min, and then concentrated. The residue waspurified using prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₀H₁₇FN₇ (M+H)⁺:m/z=374.2; found: 374.1.

Example 75.3-(4-(4-Ethylpiperazin-1-yl)phenyl)-5-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

This compound was prepared according to the procedure described inExample 74, using1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazineinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asthe starting material. LCMS calculated for C₂₈H₂₉FN₇ (M+H)⁺: m/z=482.2;found: 482.2.

Example 76.5-(6-Fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

This compound was prepared according to the procedure described inExample 74 (step 7), using1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineinstead of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asthe starting material. LCMS calculated for C₂₆H₂₆FN₈ (M+H)⁺: m/z=469.2;found: 469.2.

Example 77.5-(2-Fluoro-6-methylphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine-6-carbonitrile

This compound was prepared according to the procedure described inExample 62 (step 8), using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleinstead of1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₁₈H₁₄FN₆ (M+H)⁺:m/z=333.1; found: 333.1. ¹H NMR (TFA salt, 600 MHz, DMSO) δ 13.89 (br,1H), 8.85 (s, 1H), 8.36 (s, 1H), 8.05 (s, 1H), 7.49 (m, 1H), 7.28 (d,J=7.7 Hz, 1H), 7.23 (t, J=8.9 Hz, 1H), 3.91 (s, 3H), 2.14 (s, 3H).

Example A. HPK1 Kinase Binding Assay

A stock solution of 1 mM test compound was prepared in DMSO. Thecompound plate was prepared by 3-fold and 11-point serial dilutions. 0.1μL of the compound in DMSO was transferred from the compound plate tothe white 384 well polystyrene plates. The assay buffer contained 50 mMHEPES, pH 7.5, 0.01% Tween-20, 5 mM MgCl₂, 0.01% BSA, and 5 mM DTT. 5 μlof 4 nM active HPK1 (SignalChem M23-11G) prepared in the buffer wasadded to the plate. The enzyme concentration given was based on thegiven stock concentration reported by the vender. 5 μl of 18 nM tracer222 (ThermoFisher PV6121) and 4 nM LanthaScreen Eu-Anti GST antibody(ThermoFisher PV5595) were added. After one hour incubation at 25° C.,the plates were read on a PHERAstar FS plate reader (BMG Labtech). Kivalues were determined.

Compounds of the present disclosure, as exemplified in Examples, showedthe Ki values in the following ranges: +=Ki≤100 nM; ++=100 nM<Ki≤500 nM;+++=500 nM<Ki≤10000 nM.

TABLE 1 Example HPK1 Ki (nM) 1 ++ 2 ++ 3 + 4 + 5 + 6 + 7 + 8 + 9 + 10 +11 + 12 + 13 + 14 ++ 15 ++ 16 ++ 17 ++ 18 +++ 19 + 20 +++ 21 +++ 22 ++23 + 24 + 25 ++ 26 + 27 + 28 + 29 + 30 +++ 31 + 32 + 33 + 34 + 35 + 36++ 37 + 38 ++ 39 ++ 40 + 41 + 42 + 43 + 44 + 45 ++ 46 + 47 + 48 + 49 +50 + 51 +++ 52 +++ 53 ++ 54 ++ 55 + 56 +++ 57 +++ 58 ++ 59 +++ 60 +++61 + 62 + 63 + 64 + 65 + 66 + 67 + 68 + 69 + 70 + 71 + 72 + 72 + 74 +75 + 76 + 77 +

Example B. p-SLP76S376 HTRF Assay

One or more compounds of the invention can be tested using thep-SLP76S376 HTRF assay described as follows. Jurkat cells (cultured inRPMI1640 media with 10% FBS) are collected and centrifuged, followed byresuspension in appropriate media at 3×10⁶ cells/ml. The Jurkat cells(35 ul) are dispensed into each well in a 384 well plate. Test compoundsare diluted with cell culture media for 40-fold dilution (adding 39 ulcell culture media into 1 ul compound). The Jurkat cells in the wellplate are treated with the test compounds at various concentrations(adding 5 ul diluted compound into 35 ul Jurkat cells and starting from3 uM with 1:3 dilution) for 1 hour at 37° C., 5% CO₂), followed bytreatment with anti-CD3 (5 ug/ml, OKT3 clone) for 30 min. A 1:25dilution of 100× blocking reagent (from p-SLP76 ser376HTRF kit) with 4×Lysis Buffer (LB) is prepared and 15 ul of the 4×LB buffer with blockingreagent is added into each well and incubated at room temperature for 45mins with gentle shaking. The cell lysate (16 ul) is added into aGreiner white plate, treated with p-SLP76 ser376HTRF reagents (2 uldonor, 2 ul acceptor) and incubated at 4° C. for overnight. Thehomogeneous time resolved fluorescence (HTRF) is measured on a PHERAstarplate reader the next day. IC₅₀ determination is performed by fittingthe curve of percent inhibition versus the log of the inhibitorconcentration using the GraphPad Prism 5.0 software.

Example C. Isolation of CD4+ or CD8+ T Cells and Cytokine Measurement

Blood samples are collected from healthy donors. CD4+ or CD8+ T cellsare isolated by negative selection using CD4+ or CD8+ enrichment kits(lifetech, USA). The purity of the isolated CD4+ or CD8+ T cells isdetermined by flow cytometry and is routinely >80%. Cells are culturedin RPMI 1640 supplemented with 10% FCS, glutamine and antibiotics(Invitrogen Life Technologies, USA). For cytokine measurement, Jurkatcells or primary CD4+ or CD8+ T cells are plated at 200 k cells/well andare stimulated for 24 h with anti-CD3/anti-CD28 beads in the presence orabsence of testing compounds at various concentrations. 16 uL ofsupernatants are then transferred to a white detection plate andanalyzed using the human IL2 or IFNγ assay kits (Cisbio).

Example D. Treg Assay

One or more compounds can be tested using the Regulatory T-cellproliferation assay described as following. Primary CD4+/CD25− T-cellsand CD4+/CD25+ regulatory T-cells are isolated from human donatedPeripheral Blood Mononuclear Cells, using an isolated kit from ThermoFisher Scientific (11363D). CD4+/CD25− T-cells are labeled with CFSE(Thermo Fisher Scientific, C34554) following the protocol provided bythe vendor. CFSE labeled T-cells and CD4+/CD25+ regulatory T-cells arere-suspended at the concentration of 1×106 cells/ml in RPMI-1640 medium.100 μl of CFSE-labeled T-cells are mixed with or without 50 μl ofCD4+/CD25+ regulatory T-cells, treated with 5 μl of anti-CD3/CD28 beads(Thermo Fisher Scientific, 11132D) and various concentrations ofcompounds diluted in 50 μl of RPMI-1640 medium. Mixed populations ofcells are cultured for 5 days (37° C., 5% CO₂) and proliferation ofCFSE-labeled T-cells is analyzed by BD LSRFortessa X-20 using FITCchannel on the 5th day.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

What is claimed is:
 1. A compound of Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein: Cy^(A) is 5-10membered heteroaryl; wherein the 5-10 membered heteroaryl has at leastone ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of the 5-10membered heteroaryl is optionally substituted by oxo to form a carbonylgroup; and wherein the 5-10 membered heteroaryl is optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²⁰; each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹; or two R¹⁰substituents taken together with the carbon atom to which they areattached form a spiro 3-7-membered heterocycloalkyl ring, or a spiroC₃₋₆ cycloalkyl ring; wherein each spiro 3-7-membered heterocycloalkylring has at least one ring-forming carbon atom and 1, 2 or 3ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹¹; each R¹¹ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹²; each R¹² isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, 4-7membered heterocycloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 4-7membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R²⁰ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NOR^(a2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹; or two adjacent R²⁰ substituents on theCy^(A) ring, taken together with the atoms to which they are attached,form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fusedC₃₋₇ cycloalkyl ring; wherein each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1,2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of each fused 4-, 5-, 6- or7-membered heterocycloalkyl ring is optionally substituted by oxo toform a carbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹; each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²; or two R²¹ substituents taken togetherwith the carbon atom to which they are attached form a spiro3-7-membered heterocycloalkyl ring, or a spiro C₃₋₆ cycloalkyl ring;wherein each spiro 3-7-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1, 2 or 3 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each spiro 3-7-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the spiro 3-7membered heterocycloalkyl ring and spiro C₃₋₆ cycloalkyl ring are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²²; each R²² is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); each R^(a1), R^(c1) and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and5-10 membered heteroaryl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹; or any R^(c1) andR^(d1) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; each R^(b1) is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹; each R^(e1) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl,aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆ alkyl)aminosulfonyl;each R^(a2), R^(c2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹; or any R^(c2) and R^(d2) attached tothe same N atom, together with the N atom to which they are attached,form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2 or 3 substituents independently selected from R²¹;each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹; each R^(e2) is independently selected from H, CN,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl,di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl anddi(C₁₋₆ alkyl)aminosulfonyl; each R^(a3), R^(c3) and R^(d3), isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²; or any R^(c3) andR^(d3) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R¹²; each R^(b3) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²; each R^(a4), R^(c4) and R^(d4), isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R²²; or any R^(c4) andR^(d4) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R²²; each R^(b4) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²; each R^(a5), R^(c5) and R^(d5), isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyland C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(b5) is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; whereinsaid C₁₋₆ alkyl C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); each R^(a6), R^(c6) and R^(d6), is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R^(g) isindependently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂alkylene, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl,H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino; and n is1, 2, 3, or 4; provided that: when R¹⁰ is halo, then Cy^(A) is otherthan unsubstituted or substituted 4H-1,2,4-triazol-3-yl.
 2. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein eachR¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, CN, NO₂,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹¹.
 3. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹⁰is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, CN, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1), andNR^(c1)C(O)R^(b1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹.
 4. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein each R¹⁰ isindependently selected from C₁₋₆ alkyl, 4-10 membered heterocycloalkyl,C(O)R^(b1), and C(O)NR^(c1)R^(d1); wherein said C₁₋₆ alkyl and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹.
 5. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹⁰is independently selected from C₁₋₆ alkyl, piperazinyl, piperidinyl,morpholinyl, C(O)R^(b1), and C(O)NR^(c1)R^(d1); wherein said C₁₋₆ alkyl,piperazinyl, and piperidinyl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹¹.
 6. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹⁰is independently selected from C₁₋₆ alkyl, piperazinyl, piperidinyl,C(O)R^(b1), and C(O)NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, piperazinyl,and piperidinyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹.
 7. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein each R¹¹ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl,5-10 membered heteroaryl, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), S(O)R^(b3), S(O)NR^(c3)R^(d3),S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹².
 8. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, OR^(a3), C(O)R^(b3), andS(O)₂R^(b3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹².
 9. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R¹¹ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, C(O)R^(b3), and S(O)₂R^(b3); wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1,2, 3, or 4 substituents independently selected from R¹².
 10. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R¹¹ is independently selected from C₁₋₆ alkyl, OR^(a3),C(O)R^(b3), and S(O)₂R^(b3).
 11. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R¹¹ isindependently selected from C₁₋₆ alkyl, C(O)R^(b3), and S(O)₂R^(b3). 12.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R¹⁰ is independently selected from 4-methylpiperazin-1-yl,N-methylaminocarbonyl, methyl, N-(1-methylpiperidin-4-yl)aminocarbonyl,(4-methylpiperazin-1-yl)carbonyl, N-phenylaminocarbonyl, piperidin-4-yl,1-(methylsulfonyl)piperidin-4-yl, 1-acetyl-piperidin-4-yl, morpholinyl,4-ethylpiperazin-1-yl, or 2-hydroxypropan-2-yl.
 13. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹⁰is independently selected from 4-methylpiperazin-1-yl,N-methylaminocarbonyl, methyl, N-(1-methylpiperidin-4-yl)aminocarbonyl,(4-methylpiperazin-1-yl)carbonyl, N-phenylaminocarbonyl, piperidin-4-yl,1-(methylsulfonyl)piperidin-4-yl, and 1-acetyl-piperidin-4-yl.
 14. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Cy^(A) is 1H-indazol-4-yl, pyridin-3-yl, pyridin-4-yl,pyrimidin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, pyridin-2(1H)-on-5-yl,3H-imidazo[4,5-b]pyridin-6-yl, pyrido[3,2-b]pyrazin-7-yl,oxazolo[5,4-c]pyridin-7-yl, 1H-pyrazol-4-yl,pyrazolo[1,5-a]pyridin-3-yl, quinolin-5-yl, isoquinolin-4-yl,1H-indol-4-yl, and imidazo[1,2-a]pyridin-8-yl, each of which isoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²⁰.
 15. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein: each R²⁰ is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 memberedheteroaryl, halo, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²¹; or two adjacent R²⁰substituents on the Cy^(A) ring, taken together with the atoms to whichthey are attached, form a fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring; wherein eachfused 4-, 5-, 6- or 7-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring isoptionally substituted by oxo to form a carbonyl group; and wherein thefused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and fused C₃₋₆cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹.
 16. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein: each R²⁰ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, CN, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R²¹; or twoadjacent R²⁰ substituents on the Cy^(A) ring, taken together with theatoms to which they are attached, form a fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring; wherein eachfused 4-, 5-, 6- or 7-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring isoptionally substituted by oxo to form a carbonyl group; and wherein thefused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and fused C₃₋₆cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹.
 17. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein: each R²⁰ isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, CN, OR^(a2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), and NR^(c2)S(O)₂R^(b2); wherein saidC₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹; or two adjacent R²⁰ substituents on the Cy^(A) ring, taken togetherwith the atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹.
 18. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein: each R²⁰ is independently selected from methoxy,methyl, fluoro, trifluoromethyl, amino, methoxy, hydroxymethyl,ethoxycarbonyl, methanesulfonamino, hydroxyl, N-methylaminocarbonyl,dimethylamino, cyano, methoxycarbonyl, acetylamino, phenyl, 2-oxazolyl,tert-butyl, aminocarbonyl, N-benzylaminocarbonyl,N-(pyridin-4-ylmethyl)aminocarbonyl, ethyl, methylaminomethyl; or twoadjacent R²⁰ substituents on the Cy^(A) ring, taken together with theatoms to which they are attached, form a fused 5- or 6-memberedheterocycloalkyl ring, or a fused C₅ cycloalkyl ring; wherein each fused5- or 6-membered heterocycloalkyl ring has at least one ring-formingcarbon atom and 1 or 2 ring-forming heteroatoms independently selectedfrom N and O; wherein a ring-forming carbon atom of each fused 5- or6-membered heterocycloalkyl ring is optionally substituted by oxo toform a carbonyl group; and wherein the fused 5- or 6-memberedheterocycloalkyl ring and fused C₅ cycloalkyl ring are each optionallysubstituted with 1 or 2 substituents independently selected from amino,methylamino, 2-hydroxyethylamino, and N-benzylamino.
 19. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein: eachR²⁰ is independently selected from methoxy, methyl, fluoro,trifluoromethyl, amino, methoxy, hydroxymethyl, ethoxycarbonyl,methanesulfonamino, hydroxyl, N-methylaminocarbonyl, dimethylamino,cyano, methoxycarbonyl, acetylamino, phenyl, 2-oxazolyl, tert-butyl,aminocarbonyl, N-benzylaminocarbonyl,N-(pyridin-4-ylmethyl)aminocarbonyl, and ethyl; or two adjacent R²⁰substituents on the Cy^(A) ring, taken together with the atoms to whichthey are attached, form a fused 5- or 6-membered heterocycloalkyl ring,or a fused C₅ cycloalkyl ring; wherein each fused 5- or 6-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1 or2 ring-forming heteroatoms independently selected from N and O; whereina ring-forming carbon atom of each fused 5- or 6-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 5- or 6-membered heterocycloalkylring and fused C₅ cycloalkyl ring are each optionally substituted with 1or 2 substituents independently selected from amino, methylamino,2-hydroxyethylamino, and N-benzylamino.
 20. The compound of claim 1having Formula IIIa:

or a pharmaceutically acceptable salt thereof.
 21. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein: Cy^(A) is5-10 membered heteroaryl; wherein the 5-membered heteroaryl has at leastone ring-forming carbon atom and 1 or 2 ring-forming heteroatomsindependently selected from N, O, and S and the 6-10 membered heteroarylhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; wherein a ring-forming carbon atom of the 5-10membered heteroaryl is optionally substituted by oxo to form a carbonylgroup; and wherein the 5-10 membered heteroaryl is optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²⁰; each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, piperazinyl,piperidinyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo, CN, NO₂,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, piperazinyl, piperidinyl, C₆₋₁₀aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹; or two R¹⁰substituents taken together with the carbon atom to which they areattached form a spiro 3-7-membered heterocycloalkyl ring, or a spiroC₃₋₆ cycloalkyl ring; wherein each spiro 3-7-membered heterocycloalkylring has at least one ring-forming carbon atom and 1, 2 or 3ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹¹; each R¹¹ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹²; each R¹² isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, 4-7membered heterocycloalkyl, halo, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl and 4-7membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R²⁰ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NOR^(a2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹; or two adjacent R²⁰ substituents on theCy^(A) ring, taken together with the atoms to which they are attached,form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fusedC₃₋₇ cycloalkyl ring; wherein each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1,2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of each fused 4-, 5-, 6- or7-membered heterocycloalkyl ring is optionally substituted by oxo toform a carbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹; each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²; or two R²¹ substituents taken togetherwith the carbon atom to which they are attached form a spiro3-7-membered heterocycloalkyl ring, or a spiro C₃₋₆ cycloalkyl ring;wherein each spiro 3-7-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1, 2 or 3 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each spiro 3-7-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the spiro 3-7membered heterocycloalkyl ring and spiro C₃₋₆ cycloalkyl ring are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²²; each R²² is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a6),SR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl, are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); each R^(a1), R^(c1) and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and5-10 membered heteroaryl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹; or any R^(c1) andR^(d1) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; each R^(b1) is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 memberedheteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹; each R^(e1) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl,aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆ alkyl)aminosulfonyl;each R^(a2), R^(c2) and R^(d2), is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹; or any R^(c2) and R^(d2) attached tothe same N atom, together with the N atom to which they are attached,form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2 or 3 substituents independently selected from R²¹;each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹; each R^(e2) is independently selected from H, CN,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl,di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl anddi(C₁₋₆ alkyl)aminosulfonyl; each R^(a3), R^(c3) and R^(d3), isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²; or any R^(c3) andR^(d3) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R¹²; each R^(b3) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²; each R^(a4), R^(c4) and R^(d4), isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R²²; or any R^(c4) andR^(d4) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R²²; each R^(b4) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²; each R^(a5), R^(c5) and R^(d5), isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyland C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(b5) is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; whereinsaid C₁₋₆ alkyl C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); each R^(a6), R^(c6) and R^(d6), is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); and each R^(g) isindependently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂alkylene, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl,H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino.
 22. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: Cy^(A) is 5-10 membered heteroaryl; wherein the 5-memberedheteroaryl has at least one ring-forming carbon atom and 1 or 2ring-forming heteroatoms independently selected from N, O, and S and the6-10 membered heteroaryl has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the 5-10membered heteroaryl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰; each R¹⁰ is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, piperazinyl, piperidinyl, C₆₋₁₀aryl, 5-10 memberedheteroaryl, halo, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), andS(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, piperazinyl, piperidinyl, C₆₋₁₀aryl, and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹; each R¹¹ is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²; each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), andS(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R²⁰ is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 memberedheteroaryl, halo, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹; or two adjacent R²⁰ substituents on the Cy^(A) ring,taken together with the atoms to which they are attached, form a fused5- or 6-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein each fused 5- or 6-membered heterocycloalkyl ring has at leastone ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each fused 5- or 6-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the fused 5- or6-membered heterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²¹; each R²¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo,CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²²; each R²² is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), S(O)R^(b6), S(O)NR^(c6)R^(d6),S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R^(a1), R^(c1)and R^(d1) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, 4-10 membered heterocycloalkyl, andC₆₋₁₀aryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 4-10membered heterocycloalkyl and C₆₋₁₀aryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹¹; or anyR^(c1) and R^(d1) attached to the same N atom, together with the N atomto which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹; each R^(b1) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, and 4-10 membered heterocycloalkyl; wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹; each R^(a2), R^(c2) and R^(d2), is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹; each R^(b2) is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹; each R^(a3), R^(c3) and R^(d3), is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein saidC₁₋₆ alkyl C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²; each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²; each R^(a4), R^(c4)and R^(d4), is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²²; each R^(b4) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, and C₂₋₆ alkynylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²; each R^(a5), R^(c5) and R^(d5), isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyland C₁₋₆ haloalkyl; each R^(b5) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; each R^(a6),R^(c6) and R^(d6), is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; each R^(b6) is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl; and each R^(g) is independently selected from OH, NO₂, CN,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl,amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, and di(C₁₋₆ alkyl)aminosulfonyl.
 23. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein: Cy^(A)is 5-10 membered heteroaryl; wherein the 5-membered heteroaryl has atleast one ring-forming carbon atom and 1 or 2 ring-forming heteroatomsindependently selected from N, O, and S and the 6-10 membered heteroarylhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; wherein a ring-forming carbon atom of the 5-10membered heteroaryl is optionally substituted by oxo to form a carbonylgroup; and wherein the 5-10 membered heteroaryl is optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²⁰; each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, piperazinyl, piperidinyl, halo, CN,OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), and NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, piperazinyl, andpiperidinyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹; each R¹¹ is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); each R²⁰ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo, CN, OR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), and NR^(c2)S(O)₂R^(b2); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹; or two adjacent R²⁰ substituents on the Cy^(A) ring,taken together with the atoms to which they are attached, form a fused5- or 6-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein each fused 5- or 6-membered heterocycloalkyl ring has at leastone ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each fused 5- or 6-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the fused 5- or6-membered heterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²¹; each R²¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, 5-10 memberedheteroaryl, halo, OR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R²²; each R²² is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); each R^(a1),R^(c1) and R^(d1) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, 4-10 membered heterocycloalkyl,and C₆₋₁₀aryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 4-10membered heterocycloalkyl and C₆₋₁₀aryl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹¹; or anyR^(c1) and R^(d1) attached to the same N atom, together with the N atomto which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹; each R^(b1) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, and 4-10 membered heterocycloalkyl; wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹; each R^(a2), R^(c2) and R^(d2), is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹; each R^(b2) is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; eachR^(a3), R^(c3) and R^(d3), is independently selected from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; each R^(b3) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆ haloalkyl; each R^(a4), R^(c4) and R^(d4), is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, and C₂₋₆ alkynyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²; each R^(b4) is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; eachR^(a6), R^(c6) and R^(d6), is independently selected from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; and each R^(b6) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆ haloalkyl.
 24. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein: Cy^(A) is 5-10 membered heteroaryl;wherein the 5-membered heteroaryl has at least one ring-forming carbonatom and 1 or 2 ring-forming heteroatoms independently selected from N,O, and S and the 6-10 membered heteroaryl has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independentlyselected from N, O, and S; wherein the N and S are optionally oxidized;wherein a ring-forming carbon atom of the 5-10 membered heteroaryl isoptionally substituted by oxo to form a carbonyl group; and wherein the5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰; each R¹⁰ is independentlyselected from C₁₋₆ alkyl, piperazinyl, piperidinyl, C(O)R^(b1), andC(O)NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, piperazinyl, and piperidinylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; each R¹¹ is independently selected fromC₁₋₆ alkyl, OR^(a3), C(O)R^(b3), and S(O)₂R^(b3); each R²⁰ isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, CN, OR^(a2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), and NR^(c2)S(O)₂R^(b2); wherein saidC₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹; or two adjacent R²⁰ substituents on the Cy^(A) ring, taken togetherwith the atoms to which they are attached, form a fused 5- or 6-memberedheterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring; wherein eachfused 5- or 6-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each fused 5- or 6-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the fused 5- or6-membered heterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²¹; each R²¹ is independently selected from C₆₋₁₀ aryl,5-10 membered heteroaryl, OR^(a4), and NR^(c4)R^(d4); each R²² isOR^(a6); each R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, 4-10 membered heterocycloalkyl, and C₆₋₁₀aryl; wherein said C₁₋₆alkyl, 4-10 membered heterocycloalkyl and C₆₋₁₀ aryl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹; or any R^(c1) and R^(d1) attached to the same N atom, together withthe N atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹¹; R^(b1) is 4-10 memberedheterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; each R^(a2), R^(c2) and R^(d2) isindependently H or C₁₋₆ alkyl; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹; each R^(b2) is C₁₋₆ alkyl; each R^(b3) is C₁₋₆ alkyl; each R^(a3)is independently H or C₁₋₆ alkyl; each R^(a4), R^(c4) and R^(d4) is H orC₁₋₆ alkyl; wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 substituents independently selected from R²²; and R^(a6) is H.25. The compound of claim 1 selected from:5-(1H-Indazol-4-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-idine;3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(pyridin-3-yl)-1H-pyrazolo[4,3-idine;3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(pyridin-4-yl)-1H-pyrazolo[4,3-idine;3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(pyrimidin-5-yl)-1H-pyrazolo[4,3-idine;5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-yrrolo[2,3-b]pyridin-2(3H)-one;1′-Methyl-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H,1′H-5,6′-bipyrazolo[4,3-idine;2-(5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-ridin-3-yl)oxazole;1-Methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-idin-5-yl)pyridin-2(1H)-one;5-(3-Methyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-(4-(4-methylpiperazin-1-enyl)-1H-pyrazolo[4,3-b]pyridine;7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-rido[3,2-b]pyrazine;2-tert-Butyl-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-idin-5-yl)oxazolo[5,4-c]pyridine;5-(3-Methyl-1H-pyrazol-4-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-olo[4,3-b]pyridine;3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-olo[4,3-b]pyridine;5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-inoline;4-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-b]pyridin-5-quinoline;5-(1-Methyl-1H-indol-4-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-olo[4,3-b]pyridine;5-(Imidazo[1,2-a]pyridin-8-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-olo[4,3-b]pyridine;and5-(2-Ethylimidazo[1,2-a]pyridin-8-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-yrazolo[4,3-b]pyridine;or a pharmaceutically acceptable salt thereof.
 26. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient.
 27. A method of inhibiting HPK1 activity, saidmethod comprising administering to a patient a compound of claim 1, or apharmaceutically acceptable salt thereof.